@article{vasili_endogenous_2022, title = {Endogenous {Levels} of {Alpha}-{Synuclein} {Modulate} {Seeding} and {Aggregation} in {Cultured} {Cells}}, volume = {59}, issn = {0893-7648, 1559-1182}, url = {https://link.springer.com/10.1007/s12035-021-02713-2}, doi = {10.1007/s12035-021-02713-2}, abstract = {Abstract Parkinson’s disease is a progressive neurodegenerative disorder characterized by the accumulation of misfolded alpha-synuclein in intraneuronal inclusions known as Lewy bodies and Lewy neurites. Multiple studies strongly implicate the levels of alpha-synuclein as a major risk factor for the onset and progression of Parkinson’s disease. Alpha-synuclein pathology spreads progressively throughout interconnected brain regions but the precise molecular mechanisms underlying the seeding of alpha-synuclein aggregation are still unclear. Here, using stable cell lines expressing alpha-synuclein, we examined the correlation between endogenous alpha-synuclein levels and the seeding propensity by exogenous alpha-synuclein preformed fibrils. We applied biochemical approaches and imaging methods in stable cell lines expressing alpha-synuclein and in primary neurons to determine the impact of alpha-synuclein levels on seeding and aggregation. Our results indicate that the levels of alpha-synuclein define the pattern and severity of aggregation and the extent of p-alpha-synuclein deposition, likely explaining the selective vulnerability of different cell types in synucleinopathies. The elucidation of the cellular processes involved in the pathological aggregation of alpha-synuclein will enable the identification of novel targets and the development of therapeutic strategies for Parkinson’s disease and other synucleinopathies.}, language = {en}, number = {2}, urldate = {2022-04-13}, journal = {Molecular Neurobiology}, author = {Vasili, Eftychia and Dominguez-Meijide, Antonio and Flores-León, Manuel and Al-Azzani, Mohammed and Kanellidi, Angeliki and Melki, Ronald and Stefanis, Leonidas and Outeiro, Tiago Fleming}, month = feb, year = {2022}, keywords = {peer-reviewed}, pages = {1273--1284}, } @article{kaeser_csf_2021, title = {{CSF} p-tau increase in response to {Aβ}-type and {Danish}-type cerebral amyloidosis and in the absence of neurofibrillary tangles}, issn = {0001-6322, 1432-0533}, url = {https://link.springer.com/10.1007/s00401-021-02400-5}, doi = {10.1007/s00401-021-02400-5}, language = {en}, urldate = {2022-01-03}, journal = {Acta Neuropathologica}, author = {Kaeser, Stephan A. and Häsler, Lisa M. and Lambert, Marius and Bergmann, Carina and Bottelbergs, Astrid and Theunis, Clara and Mercken, Marc and Jucker, Mathias}, month = dec, year = {2021}, keywords = {peer-reviewed}, } @article{schweighauser_structures_2020, title = {Structures of α-synuclein filaments from multiple system atrophy}, volume = {585}, issn = {0028-0836, 1476-4687}, url = {http://www.nature.com/articles/s41586-020-2317-6}, doi = {10.1038/s41586-020-2317-6}, language = {en}, number = {7825}, urldate = {2021-02-24}, journal = {Nature}, author = {Schweighauser, Manuel and Shi, Yang and Tarutani, Airi and Kametani, Fuyuki and Murzin, Alexey G. and Ghetti, Bernardino and Matsubara, Tomoyasu and Tomita, Taisuke and Ando, Takashi and Hasegawa, Kazuko and Murayama, Shigeo and Yoshida, Mari and Hasegawa, Masato and Scheres, Sjors H. W. and Goedert, Michel}, month = sep, year = {2020}, keywords = {highlight, peer-reviewed}, pages = {464--469}, } @article{mavroeidi_endogenous_2019, title = {Endogenous oligodendroglial alpha-synuclein and {TPPP}/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models}, volume = {138}, issn = {0001-6322, 1432-0533}, url = {http://link.springer.com/10.1007/s00401-019-02014-y}, doi = {10.1007/s00401-019-02014-y}, language = {en}, number = {3}, urldate = {2021-03-26}, journal = {Acta Neuropathologica}, author = {Mavroeidi, Panagiota and Arvanitaki, Fedra and Karakitsou, Anastasia-Kiriaki and Vetsi, Maria and Kloukina, Ismini and Zweckstetter, Markus and Giller, Karin and Becker, Stefan and Sorrentino, Zachary A. and Giasson, Benoit I. and Jensen, Poul Henning and Stefanis, Leonidas and Xilouri, Maria}, month = sep, year = {2019}, keywords = {highlight, peer-reviewed}, pages = {415--441}, } @article{falcon_structures_2018, title = {Structures of filaments from {Pick}’s disease reveal a novel tau protein fold}, volume = {561}, issn = {0028-0836, 1476-4687}, url = {http://www.nature.com/articles/s41586-018-0454-y}, doi = {10.1038/s41586-018-0454-y}, language = {en}, number = {7721}, urldate = {2018-12-11}, journal = {Nature}, author = {Falcon, Benjamin and Zhang, Wenjuan and Murzin, Alexey G. and Murshudov, Garib and Garringer, Holly J. and Vidal, Ruben and Crowther, R. Anthony and Ghetti, Bernardino and Scheres, Sjors H. W. and Goedert, Michel}, month = sep, year = {2018}, keywords = {highlight, peer-reviewed}, pages = {137--140}, } @article{laferriere_similar_2022, title = {Similar neuronal imprint and no cross-seeded fibrils in α-synuclein aggregates from {MSA} and {Parkinson}’s disease}, volume = {8}, issn = {2373-8057}, url = {https://www.nature.com/articles/s41531-021-00264-w}, doi = {10.1038/s41531-021-00264-w}, abstract = {Abstract Aggregated alpha-synuclein (α-syn) is a principal constituent of Lewy bodies (LBs) and glial cytoplasmic inclusions (GCIs) observed respectively inside neurons in Parkinson’s disease (PD) and oligodendrocytes in multiple system atrophy (MSA). Yet, the cellular origin, the pathophysiological role, and the mechanism of formation of these inclusions bodies (IBs) remain to be elucidated. It has recently been proposed that α-syn IBs eventually cause the demise of the host cell by virtue of the cumulative sequestration of partner proteins and organelles. In particular, the hypothesis of a local cross-seeding of other fibrillization-prone proteins like tau or TDP-43 has also been put forward. We submitted sarkosyl-insoluble extracts of post-mortem brain tissue from PD, MSA and control subjects to a comparative proteomic analysis to address these points. Our studies indicate that: (i) α-syn is by far the most enriched protein in PD and MSA extracts compared to controls; (ii) PD and MSA extracts share a striking overlap of their sarkosyl-insoluble proteomes, consisting of a vast majority of mitochondrial and neuronal synaptic proteins, and (iii) other fibrillization-prone protein candidates possibly cross-seeded by α-syn are neither found in PD nor MSA extracts. Thus, our results (i) support the idea that pre-assembled building blocks originating in neurons serve to the formation of GCIs in MSA, (ii) show no sign of amyloid cross-seeding in either synucleinopathy, and (iii) point to the sequestration of mitochondria and of neuronal synaptic components in both LBs and GCIs.}, language = {en}, number = {1}, urldate = {2022-02-09}, journal = {npj Parkinson's Disease}, author = {Laferrière, Florent and Claverol, Stéphane and Bezard, Erwan and De Giorgi, Francesca and Ichas, François}, month = dec, year = {2022}, keywords = {peer-reviewed}, pages = {10}, } @article{laferriere_overexpression_2020, title = {Overexpression of α-{Synuclein} by {Oligodendrocytes} in {Transgenic} {Mice} {Does} {Not} {Recapitulate} the {Fibrillar} {Aggregation} {Seen} in {Multiple} {System} {Atrophy}}, volume = {9}, copyright = {http://creativecommons.org/licenses/by/3.0/}, url = {https://www.mdpi.com/2073-4409/9/11/2371}, doi = {10.3390/cells9112371}, abstract = {The synucleinopathy underlying multiple system atrophy (MSA) is characterized by the presence of abundant amyloid inclusions containing fibrillar \α-synuclein (\α-syn) aggregates in the brains of the patients and is associated with an extensive neurodegeneration. In contrast to Parkinson\’s disease (PD) where the pathological \α-syn aggregates are almost exclusively neuronal, the \α-syn inclusions in MSA are principally observed in oligodendrocytes (OLs) where they form glial cytoplasmic inclusions (GCIs). This is intriguing because differentiated OLs express low levels of \α-syn, yet pathogenic amyloid \α-syn seeds require significant amounts of \α-syn monomers to feed their fibrillar growth and to eventually cause the buildup of cytopathological inclusions. One of the transgenic mouse models of this disease is based on the targeted overexpression of human \α-syn in OLs using the PLP promoter. In these mice, the histopathological images showing a rapid emergence of S129-phosphorylated \α-syn inside OLs are considered as equivalent to GCIs. Instead, we report here that they correspond to the accumulation of phosphorylated \α-syn monomers/oligomers and not to the appearance of the distinctive fibrillar \α-syn aggregates that are present in the brains of MSA or PD patients. In spite of a propensity to co-sediment with myelin sheath contaminants, the phosphorylated forms found in the brains of the transgenic animals are soluble (\>80\%). In clear contrast, the phosphorylated species present in the brains of MSA and PD patients are insoluble fibrils (\>95\%). Using primary cultures of OLs from PLP-\αSyn mice we observed a variable association of S129-phosphorylated \α-syn with the cytoplasmic compartment, the nucleus and with membrane domains suggesting that OLs functionally accommodate the phospho-\α-syn deriving from experimental overexpression. Yet and while not taking place spontaneously, fibrillization can be seeded in these primary cultures by challenging the OLs with \α-syn preformed fibrils (PFFs). This indicates that a targeted overexpression of \α-syn does not model GCIs in mice but that it can provide a basis for seeding aggregation using PFFs. This approach could help establishing a link between \α-syn aggregation and the development of a clinical phenotype in these transgenic animals.}, language = {en}, number = {11}, urldate = {2021-01-13}, journal = {Cells}, author = {Laferrière, Florent and He, Xin and Zinghirino, Federica and Doudnikoff, Evelyne and Faggiani, Emilie and Meissner, Wassilios G. and Bezard, Erwan and De Giorgi, Francesca and Ichas, François}, month = nov, year = {2020}, note = {Number: 11 Publisher: Multidisciplinary Digital Publishing Institute}, keywords = {GCIs, multiple system atrophy, peer-reviewed, α-synuclein}, pages = {2371}, } @article{zhang_novel_2020, title = {Novel tau filament fold in corticobasal degeneration}, volume = {580}, issn = {0028-0836, 1476-4687}, url = {http://www.nature.com/articles/s41586-020-2043-0}, doi = {10.1038/s41586-020-2043-0}, language = {en}, number = {7802}, urldate = {2022-03-07}, journal = {Nature}, author = {Zhang, Wenjuan and Tarutani, Airi and Newell, Kathy L. and Murzin, Alexey G. and Matsubara, Tomoyasu and Falcon, Benjamin and Vidal, Ruben and Garringer, Holly J. and Shi, Yang and Ikeuchi, Takeshi and Murayama, Shigeo and Ghetti, Bernardino and Hasegawa, Masato and Goedert, Michel and Scheres, Sjors H. W.}, month = apr, year = {2020}, keywords = {highlight, peer-reviewed}, pages = {283--287}, } @article{falcon_novel_2019, title = {Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules}, volume = {568}, issn = {0028-0836}, url = {https://www.nature.com/articles/s41586-019-1026-5}, doi = {10.1038/s41586-019-1026-5}, abstract = {Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers–, CTE has since been identified in former participants of other contact sports, ex-military personnel and following physical abuse–. No disease-modifying therapies exist and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels,. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer’s disease and other tauopathies,. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. We used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments, with resolutions down to 2.3 Å, from the brains of three individuals with CTE, one American football player and two boxers. We show that filament structures are identical in the three cases, but distinct from those of Alzheimer’s and Pick’s diseases, and from those formed in vitro–. Like in Alzheimer's disease,,–, all six brain tau isoforms assemble into CTE filaments, and residues K274/S305-R379 form the ordered core of two identical C-shaped protofilaments. However, CTE filaments have novel protofilament interfaces, resulting in different overall morphologies. Moreover, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from Alzheimer's disease brain. This cavity encloses an additional density that is not connected to tau, suggesting that incorporation of cofactors may play a role in tau aggregation in CTE. The tau filament structures presented here provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.}, number = {7752}, urldate = {2020-04-21}, journal = {Nature}, author = {Falcon, Benjamin and Zivanov, Jasenko and Zhang, Wenjuan and Murzin, Alexey G. and Garringer, Holly J. and Vidal, Ruben and Crowther, R. Anthony and Newell, Kathy L. and Ghetti, Bernardino and Goedert, Michel and Scheres, Sjors H.W.}, month = apr, year = {2019}, pmid = {30894745}, pmcid = {PMC6472968}, keywords = {peer-reviewed}, pages = {420--423}, } @article{melki_les_2020, title = {Les protéinopathies infectieuses de {Parkinson} et d’{Alzheimer}}, volume = {204}, issn = {00014079}, url = {https://linkinghub.elsevier.com/retrieve/pii/S0001407920300182}, doi = {10.1016/j.banm.2019.12.019}, language = {fr}, number = {3}, urldate = {2021-03-25}, journal = {Bulletin de l'Académie Nationale de Médecine}, author = {Melki, R.}, month = mar, year = {2020}, keywords = {peer-reviewed}, pages = {224--231}, } @article{emmenegger_lag3_2021, title = {{LAG3} is not expressed in human and murine neurons and does not modulate α‐synucleinopathies}, volume = {13}, issn = {1757-4676, 1757-4684}, url = {https://onlinelibrary.wiley.com/doi/10.15252/emmm.202114745}, doi = {10.15252/emmm.202114745}, language = {en}, number = {9}, urldate = {2022-02-09}, journal = {EMBO Molecular Medicine}, author = {Emmenegger, Marc and De Cecco, Elena and Hruska‐Plochan, Marian and Eninger, Timo and Schneider, Matthias M and Barth, Melanie and Tantardini, Elena and de Rossi, Pierre and Bacioglu, Mehtap and Langston, Rebekah G and Kaganovich, Alice and Bengoa‐Vergniory, Nora and Gonzalez‐Guerra, Andrès and Avar, Merve and Heinzer, Daniel and Reimann, Regina and Häsler, Lisa M and Herling, Therese W and Matharu, Naunehal S and Landeck, Natalie and Luk, Kelvin and Melki, Ronald and Kahle, Philipp J and Hornemann, Simone and Knowles, Tuomas P J and Cookson, Mark R and Polymenidou, Magdalini and Jucker, Mathias and Aguzzi, Adriano}, month = sep, year = {2021}, keywords = {peer-reviewed}, } @article{zhang_heparin-induced_2019, title = {Heparin-induced tau filaments are polymorphic and differ from those in {Alzheimer}’s and {Pick}’s diseases}, volume = {8}, issn = {2050-084X}, url = {https://elifesciences.org/articles/43584}, doi = {10.7554/eLife.43584}, abstract = {Assembly of microtubule-associated protein tau into filamentous inclusions underlies a range of neurodegenerative diseases. Tau filaments adopt different conformations in Alzheimer’s and Pick’s diseases. Here, we used cryo- and immuno- electron microscopy to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 2N4R tau assembles into multiple types of filaments, and the structures of three types reveal similar ‘kinked hairpin’ folds, in which the second and third repeats pack against each other. 2N3R tau filaments are structurally homogeneous, and adopt a dimeric core, where the third repeats of two tau molecules pack in a parallel manner. The heparin-induced tau filaments differ from those of Alzheimer’s or Pick’s disease, which have larger cores with different repeat compositions. Our results illustrate the structural versatility of amyloid filaments, and raise questions about the relevance of in vitro assembly.}, language = {en}, urldate = {2022-03-14}, journal = {eLife}, author = {Zhang, Wenjuan and Falcon, Benjamin and Murzin, Alexey G and Fan, Juan and Crowther, R Anthony and Goedert, Michel and Scheres, Sjors HW}, month = feb, year = {2019}, pages = {e43584}, } @article{pantazopoulou_distinct_2020, title = {Distinct alpha‐{Synuclein} species induced by seeding are selectively cleared by the {Lysosome} or the {Proteasome} in neuronally differentiated {SH}‐{SY5Y} cells}, issn = {0022-3042, 1471-4159}, url = {https://onlinelibrary.wiley.com/doi/10.1111/jnc.15174}, doi = {10.1111/jnc.15174}, language = {en}, urldate = {2020-11-20}, journal = {Journal of Neurochemistry}, author = {Pantazopoulou, Marina and Brembati, Viviana and Kanellidi, Angeliki and Bousset, Luc and Melki, Ronald and Stefanis, Leonidas}, month = sep, year = {2020}, keywords = {highlight, peer-reviewed}, pages = {jnc.15174}, } @article{fenyi_assessment_2018, title = {Assessment of the efficacy of different procedures that remove and disassemble alpha-synuclein, tau and {A}-beta fibrils from laboratory material and surfaces}, volume = {8}, issn = {2045-2322}, url = {https://www.nature.com/articles/s41598-018-28856-2}, doi = {10.1038/s41598-018-28856-2}, abstract = {α-synuclein fibrillar polymorphs, Tau and Aß 1-42 fibrillar assemblies have been shown to propagate, amplify and trigger the formation of protein deposits reminiscent of those present within the central nervous system of patients developing synucleinopathies, tauopathies and amyloid plaques after injection intracerebrally, intramuscularly, intraperitoneally or within the blood stream of model animals. They are thus hazardous and there is need for decontamination and inactivation procedures for laboratory surfaces and non-disposable material. We assessed the effectiveness of different reagents to clean and disassemble potentially pathogenic assemblies adsorbed on non-disposable materials in laboratories. We show that commercial detergents and SDS are way more suited to detach α-synuclein fibrillar polymorphs, Tau and Aß 1-42 fibrillar assemblies from contaminated surfaces and disassemble the fibrils than methods designed to decrease PrP prion infectivity. Our observations reveal that the choice of the most adapted cleaning procedure for one given protein assembly or fibrillar polymorph should integrate detergent's cleaning efficiency, material compatibility and capacity to dismantle assemblies. We provide an integrated representation where desorption and neutralization efficacy and surface compatibility are combined to facilitate the choice of the most adapted decontamination procedure. This representation, together with good laboratory practices, contributes to reducing potential health hazards associated to manipulating protein assemblies with prion-like properties.}, language = {eng}, number = {1}, journal = {Scientific Reports}, author = {Fenyi, Alexis and Coens, Audrey and Bellande, Tracy and Melki, Ronald and Bousset, Luc}, month = jul, year = {2018}, pmid = {30018327}, pmcid = {PMC6050226}, keywords = {peer-reviewed}, pages = {10788}, } @article{uhlmann_acute_2020, title = {Acute targeting of pre-amyloid seeds in transgenic mice reduces {Alzheimer}-like pathology later in life}, volume = {23}, issn = {1097-6256, 1546-1726}, url = {http://www.nature.com/articles/s41593-020-00737-w}, doi = {10.1038/s41593-020-00737-w}, language = {en}, number = {12}, urldate = {2021-02-25}, journal = {Nature Neuroscience}, author = {Uhlmann, Ruth E. and Rother, Christine and Rasmussen, Jay and Schelle, Juliane and Bergmann, Carina and Ullrich Gavilanes, Emily M. and Fritschi, Sarah K. and Buehler, Anika and Baumann, Frank and Skodras, Angelos and Al-Shaana, Rawaa and Beschorner, Natalie and Ye, Lan and Kaeser, Stephan A. and Obermüller, Ulrike and Christensen, Søren and Kartberg, Fredrik and Stavenhagen, Jeffrey B. and Rahfeld, Jens-Ulrich and Cynis, Holger and Qian, Fang and Weinreb, Paul H. and Bussiere, Thierry and Walker, Lary C. and Staufenbiel, Matthias and Jucker, Mathias}, month = dec, year = {2020}, keywords = {peer-reviewed}, pages = {1580--1588}, } @article{shrivastava_clustering_2019, title = {Clustering of {Tau} fibrils impairs the synaptic composition of α3‐{Na}+/{K}+‐{ATPase} and {AMPA} receptors}, copyright = {© 2019 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.}, issn = {0261-4189, 1460-2075}, url = {https://www.embopress.org/doi/full/10.15252/embj.201899871}, doi = {10.15252/embj.201899871}, abstract = {Tau assemblies have prion‐like properties: they propagate from one neuron to another and amplify by seeding the aggregation of endogenous Tau. Although key in prion‐like propagation, the binding of exogenous Tau assemblies to the plasma membrane of naïve neurons is not understood. We report that fibrillar Tau forms clusters at the plasma membrane following lateral diffusion. We found that the fibrils interact with the Na+/K+‐ATPase (NKA) and AMPA receptors. The consequence of the clustering is a reduction in the amount of α3‐NKA and an increase in the amount of GluA2‐AMPA receptor at synapses. Furthermore, fibrillar Tau destabilizes functional NKA complexes. Tau and α‐synuclein aggregates often co‐exist in patients’ brains. We now show evidences for cross‐talk between these pathogenic aggregates with α‐synuclein fibrils dramatically enhancing fibrillar Tau clustering and synaptic localization. Our results suggest that fibrillar α‐synuclein and Tau cross‐talk at the plasma membrane imbalance neuronal homeostasis. Synopsis {\textless}img class="highwire-embed" alt="Embedded Image" src="http://emboj.embopress.org/sites/default/files/highwire/embojnl/early/2019/01/08/embj.201899871/embed/graphic-1.gif"/{\textgreater} Pathogenic fibrillar Tau remodel excitatory synaptic protein composition and imbalance neuronal homeostasis. Exogenous fibrillar‐Tau clusters at excitatory synapses.The membrane interactome of fibrillar Tau is identified.Fibrillar‐Tau interacts with Na+/K+‐ATPase and GluA2‐AMPA receptor.Fibrillar Tau reduces Na+/K+‐ATPase and increases GluA2‐AMPA receptor at synapses.Synuclein fibrils cross‐talk with fibrillar‐Tau at neuronal membrane.}, language = {en}, urldate = {2019-01-11}, journal = {The EMBO Journal}, author = {Shrivastava, Amulya Nidhi and Redeker, Virginie and Pieri, Laura and Bousset, Luc and Renner, Marianne and Madiona, Karine and Mailhes‐Hamon, Caroline and Coens, Audrey and Buée, Luc and Hantraye, Philippe and Triller, Antoine and Melki, Ronald}, month = jan, year = {2019}, pmid = {30630857}, keywords = {cross‐talk of pathogenic proteins, highlight, misfolding disease, peer-reviewed, protein aggregation and clustering, single‐particle tracking, tauopathies}, pages = {e99871}, } @article{fitzpatrick_cryo-em_2017, title = {Cryo-{EM} structures of tau filaments from {Alzheimer}’s disease}, volume = {547}, issn = {0028-0836, 1476-4687}, url = {http://www.nature.com/doifinder/10.1038/nature23002}, doi = {10.1038/nature23002}, number = {7662}, urldate = {2018-11-26}, journal = {Nature}, author = {Fitzpatrick, Anthony W. P. and Falcon, Benjamin and He, Shaoda and Murzin, Alexey G. and Murshudov, Garib and Garringer, Holly J. and Crowther, R. Anthony and Ghetti, Bernardino and Goedert, Michel and Scheres, Sjors H. W.}, month = jul, year = {2017}, keywords = {highlight, peer-reviewed}, pages = {185--190}, } @article{shi_cryo-em_2021, title = {Cryo-{EM} structures of tau filaments from {Alzheimer}’s disease with {PET} ligand {APN}-1607}, volume = {141}, issn = {0001-6322, 1432-0533}, url = {https://link.springer.com/10.1007/s00401-021-02294-3}, doi = {10.1007/s00401-021-02294-3}, abstract = {Abstract Tau and Aβ assemblies of Alzheimer’s disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.}, language = {en}, number = {5}, urldate = {2022-03-09}, journal = {Acta Neuropathologica}, author = {Shi, Yang and Murzin, Alexey G. and Falcon, Benjamin and Epstein, Alexander and Machin, Jonathan and Tempest, Paul and Newell, Kathy L. and Vidal, Ruben and Garringer, Holly J. and Sahara, Naruhiko and Higuchi, Makoto and Ghetti, Bernardino and Jang, Ming-Kuei and Scheres, Sjors H. W. and Goedert, Michel}, month = may, year = {2021}, pages = {697--708}, } @article{shrivastava_differential_2020, title = {Differential {Membrane} {Binding} and {Seeding} of {Distinct} α-{Synuclein} {Fibrillar} {Polymorphs}}, volume = {118}, issn = {0006-3495}, url = {https://www.cell.com/biophysj/abstract/S0006-3495(20)30069-2}, doi = {10.1016/j.bpj.2020.01.022}, language = {English}, number = {6}, urldate = {2020-03-23}, journal = {Biophysical Journal}, author = {Shrivastava, Amulya Nidhi and Bousset, Luc and Renner, Marianne and Redeker, Virginie and Savistchenko, Jimmy and Triller, Antoine and Melki, Ronald}, month = jan, year = {2020}, pmid = {32059758}, note = {Publisher: Elsevier}, keywords = {highlight, peer-reviewed}, pages = {1301--1320}, } @article{shi_structure-based_2021, title = {Structure-based classification of tauopathies}, volume = {598}, issn = {0028-0836, 1476-4687}, url = {https://www.nature.com/articles/s41586-021-03911-7}, doi = {10.1038/s41586-021-03911-7}, language = {en}, number = {7880}, urldate = {2021-10-20}, journal = {Nature}, author = {Shi, Yang and Zhang, Wenjuan and Yang, Yang and Murzin, Alexey G. and Falcon, Benjamin and Kotecha, Abhay and van Beers, Mike and Tarutani, Airi and Kametani, Fuyuki and Garringer, Holly J. and Vidal, Ruben and Hallinan, Grace I. and Lashley, Tammaryn and Saito, Yuko and Murayama, Shigeo and Yoshida, Mari and Tanaka, Hidetomo and Kakita, Akiyoshi and Ikeuchi, Takeshi and Robinson, Andrew C. and Mann, David M. A. and Kovacs, Gabor G. and Revesz, Tamas and Ghetti, Bernardino and Hasegawa, Masato and Goedert, Michel and Scheres, Sjors H. W.}, month = oct, year = {2021}, keywords = {highlight, peer-reviewed}, pages = {359--363}, } @article{fenyi_detection_2019, title = {Detection of alpha-synuclein aggregates in gastrointestinal biopsies by protein misfolding cyclic amplification}, volume = {129}, issn = {0969-9961}, url = {http://www.sciencedirect.com/science/article/pii/S0969996119301172}, doi = {10.1016/j.nbd.2019.05.002}, abstract = {Lewy bodies and neurites, the pathological signatures found in the central nervous system of Parkinson's disease (PD) patients, are primarily composed of aggregated alpha-synuclein (aSyn). The observation that aSyn aggregates are also found in the enteric nervous system has prompted several studies aimed at developing a diagnostic procedure based on the detection of pathological aSyn in gastrointestinal (GI) biopsies. The existing studies, which have all used immunohistochemistry for the detection of pathological aSyn, have had conflicting results. In the current survey, we analyzed the seeding propensity of aSyn aggregates from GI biopsies. A total of 29 subjects participated to this study, 18 PD patients and 11 controls. For each patient, 2 to 4 GI biopsies were taken from the same site (antrum, sigmoid colon or rectum) and used to seed the aggregation of recombinant aSyn in an assay inspired from the protein misfolding cyclic amplification (PMCA) method. In a subset of patients and controls (14 and 3, respectively), one or two additional biopsies were analyzed by immunohistochemistry for the presence of phosphorylated aSyn histopathology (PASH) using antibodies against phosphorylated aSyn and PGP 9.5. Except for one subject, none of the control samples seeded aSyn aggregation in PMCA reaction. GI biopsies from patients with PD seeded aSyn aggregation in 10 out of 18 cases (7 from the sigmoid colon, 2 from the antrum and one from the rectum). There was good agreement between PMCA and immunohistochemistry results as, except for two cases, all PMCA-positive PD patients were also PASH-positive. Our findings show that the PMCA method we implemented is capable of detecting aSyn aggregates in routine GI biopsies. They also suggest that rectum biopsies do not contain sufficient amounts of aggregated aSyn to detect seeded assembly by PMCA. While encouraging, our findings indicate that further studies are needed to establish the diagnostic potential of the PMCA method we implemented to detect aSyn aggregates in upper GI biopsies.}, language = {en}, urldate = {2019-12-02}, journal = {Neurobiology of Disease}, author = {Fenyi, Alexis and Leclair-Visonneau, Laurène and Clairembault, Thomas and Coron, Emmanuel and Neunlist, Michel and Melki, Ronald and Derkinderen, Pascal and Bousset, Luc}, month = sep, year = {2019}, keywords = {Alpha-synuclein, Biopsy, Enteric nervous system, Gut, Parkinson's disease, Protein misfolding cyclic amplification, highlight, peer-reviewed}, pages = {38--43}, } @article{guerrero-ferreira_two_2019, title = {Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy}, volume = {8}, issn = {2050-084X}, url = {https://doi.org/10.7554/eLife.48907}, doi = {10.7554/eLife.48907}, abstract = {Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1-121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50-57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.}, urldate = {2019-12-10}, journal = {eLife}, author = {Guerrero-Ferreira, Ricardo and Taylor, Nicholas MI and Arteni, Ana-Andreea and Kumari, Pratibha and Mona, Daniel and Ringler, Philippe and Britschgi, Markus and Lauer, Matthias E and Makky, Ali and Verasdonck, Joeri and Riek, Roland and Melki, Ronald and Meier, Beat H and Böckmann, Anja and Bousset, Luc and Stahlberg, Henning}, editor = {Scheres, Sjors HW}, month = dec, year = {2019}, keywords = {highlight, peer-reviewed}, pages = {e48907}, } @article{van_der_perren_structural_2020, title = {The structural differences between patient-derived α-synuclein strains dictate characteristics of {Parkinson}’s disease, multiple system atrophy and dementia with {Lewy} bodies}, volume = {139}, issn = {1432-0533}, url = {https://doi.org/10.1007/s00401-020-02157-3}, doi = {10.1007/s00401-020-02157-3}, abstract = {Synucleinopathies, such as Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct αSYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of αSYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human αSYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified αSYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of αSYN fibrils dictates synucleinopathies characteristics. We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, αSYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provoking the most aggressive phenotype and more similarities with PD compared to DLB strains.}, language = {en}, number = {6}, urldate = {2020-06-02}, journal = {Acta Neuropathologica}, author = {Van der Perren, Anke and Gelders, Géraldine and Fenyi, Alexis and Bousset, Luc and Brito, Filipa and Peelaerts, Wouter and Van den Haute, Chris and Gentleman, Steve and Melki, Ronald and Baekelandt, Veerle}, month = jun, year = {2020}, keywords = {highlight, peer-reviewed}, pages = {977--1000}, } @article{tanriover_prominent_2020, title = {Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions}, volume = {8}, issn = {2051-5960}, url = {https://doi.org/10.1186/s40478-020-00993-8}, doi = {10.1186/s40478-020-00993-8}, abstract = {Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated α-synuclein (αS). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of αS but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study αS conformers among different transgenic (TG) mouse models of α-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]αS; Thy1-h[A53T]αS; Thy1-h[A30P]αS; Thy1-mαS) that overexpress human or murine αS and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal αS pathology as evidenced by accumulation of αS serine 129 (p-αS) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study αS conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal αS pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of αS, but were largely p-αS-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded αS aggregation. Although nature and significance of microglial inclusions for human α-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of α-synucleinopathy bears importance for mechanistic and preclinical-translational studies.}, number = {1}, urldate = {2020-08-17}, journal = {Acta Neuropathologica Communications}, author = {Tanriöver, Gaye and Bacioglu, Mehtap and Schweighauser, Manuel and Mahler, Jasmin and Wegenast-Braun, Bettina M. and Skodras, Angelos and Obermüller, Ulrike and Barth, Melanie and Kronenberg-Versteeg, Deborah and Nilsson, K. Peter R. and Shimshek, Derya R. and Kahle, Philipp J. and Eisele, Yvonne S. and Jucker, Mathias}, month = aug, year = {2020}, keywords = {highlight, peer-reviewed}, pages = {133}, } @article{dominguez-meijide_effects_2020, title = {Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization}, volume = {10}, issn = {2045-2322}, url = {http://www.nature.com/articles/s41598-020-69744-y}, doi = {10.1038/s41598-020-69744-y}, language = {en}, number = {1}, urldate = {2021-02-24}, journal = {Scientific Reports}, author = {Dominguez-Meijide, Antonio and Vasili, Eftychia and König, Annekatrin and Cima-Omori, Maria-Sol and Ibáñez de Opakua, Alain and Leonov, Andrei and Ryazanov, Sergey and Zweckstetter, Markus and Griesinger, Christian and Outeiro, Tiago F.}, month = dec, year = {2020}, keywords = {highlight, peer-reviewed}, pages = {12827}, } @article{de_giorgi_novel_2020, title = {Novel self-replicating α-synuclein polymorphs that escape {ThT} monitoring can spontaneously emerge and acutely spread in neurons}, volume = {6}, issn = {2375-2548}, url = {https://advances.sciencemag.org/lookup/doi/10.1126/sciadv.abc4364}, doi = {10.1126/sciadv.abc4364}, abstract = {The conformational strain diversity characterizing α-synuclein (α-syn) amyloid fibrils is thought to determine the different clinical presentations of neurodegenerative diseases underpinned by a synucleinopathy. Experimentally, various α-syn fibril polymorphs have been obtained from distinct fibrillization conditions by altering the medium constituents and were selected by amyloid monitoring using the probe thioflavin T (ThT). We report that, concurrent with classical ThT-positive products, fibrillization in saline also gives rise to polymorphs invisible to ThT (τ − ). The generation of τ − fibril polymorphs is stochastic and can skew the apparent fibrillization kinetics revealed by ThT. Their emergence has thus been ignored so far or mistaken for fibrillization inhibitions/failures. They present a yet undescribed atomic organization and show an exacerbated propensity toward self-replication in cortical neurons, and in living mice, their injection into the substantia nigra pars compacta triggers a synucleinopathy that spreads toward the dorsal striatum, the nucleus accumbens, and the insular cortex.}, language = {en}, number = {40}, urldate = {2021-02-24}, journal = {Science Advances}, author = {De Giorgi, Francesca and Laferrière, Florent and Zinghirino, Federica and Faggiani, Emilie and Lends, Alons and Bertoni, Mathilde and Yu, Xuan and Grélard, Axelle and Morvan, Estelle and Habenstein, Birgit and Dutheil, Nathalie and Doudnikoff, Evelyne and Daniel, Jonathan and Claverol, Stéphane and Qin, Chuan and Loquet, Antoine and Bezard, Erwan and Ichas, François}, month = oct, year = {2020}, keywords = {highlight, peer-reviewed}, pages = {eabc4364}, } @article{fenyi_seeding_2021, title = {Seeding {Propensity} and {Characteristics} of {Pathogenic} α{Syn} {Assemblies} in {Formalin}-{Fixed} {Human} {Tissue} from the {Enteric} {Nervous} {System}, {Olfactory} {Bulb}, and {Brainstem} in {Cases} {Staged} for {Parkinson}’s {Disease}}, volume = {10}, issn = {2073-4409}, url = {https://www.mdpi.com/2073-4409/10/1/139}, doi = {10.3390/cells10010139}, abstract = {We investigated α-synuclein’s (αSyn) seeding activity in tissue from the brain and enteric nervous system. Specifically, we assessed the seeding propensity of pathogenic αSyn in formalin-fixed tissue from the gastric cardia and five brain regions of 29 individuals (12 Parkinson’s disease, 8 incidental Lewy body disease, 9 controls) using a protein misfolding cyclic amplification assay. The structural characteristics of the resultant αSyn assemblies were determined by limited proteolysis and transmission electron microscopy. We show that fixed tissue from Parkinson’s disease (PD) and incidental Lewy body disease (ILBD) seeds the aggregation of monomeric αSyn into fibrillar assemblies. Significant variations in the characteristics of fibrillar assemblies derived from different regions even within the same individual were observed. This finding suggests that fixation stabilizes seeds with an otherwise limited seeding propensity, that yield assemblies with different intrinsic structures (i.e., strains). The lag phase preceding fibril assembly for patients ≥80 was significantly shorter than in other age groups, suggesting the existence of increased numbers of seeds or a higher seeding potential of pathogenic αSyn with time. Seeding activity did not diminish in late-stage disease. No statistically significant difference in the seeding efficiency of specific regions was found, nor was there a relationship between seeding efficiency and the load of pathogenic αSyn in a particular region at a given neuropathological stage.}, language = {en}, number = {1}, urldate = {2021-03-25}, journal = {Cells}, author = {Fenyi, Alexis and Duyckaerts, Charles and Bousset, Luc and Braak, Heiko and Tredici, Kelly Del and Melki, Ronald and Neuro-CEB Neuropathology Network, on behalf of the Brainbank}, month = jan, year = {2021}, keywords = {highlight, peer-reviewed}, pages = {139}, } @article{miller_tau_2021, title = {Tau assemblies do not behave like independently acting prion-like particles in mouse neural tissue}, volume = {9}, issn = {2051-5960}, url = {https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01141-6}, doi = {10.1186/s40478-021-01141-6}, abstract = {Abstract A fundamental property of infectious agents is their particulate nature: infectivity arises from independently-acting particles rather than as a result of collective action. Assemblies of the protein tau can exhibit seeding behaviour, potentially underlying the apparent spread of tau aggregation in many neurodegenerative diseases. Here we ask whether tau assemblies share with classical pathogens the characteristic of particulate behaviour. We used organotypic hippocampal slice cultures from P301S tau transgenic mice in order to precisely control the concentration of extracellular tau assemblies in neural tissue. Whilst untreated slices displayed no overt signs of pathology, exposure to recombinant tau assemblies could result in the formation of intraneuronal, hyperphosphorylated tau structures. However, seeding ability of tau assemblies did not titrate in a one-hit manner in neural tissue. The results suggest that seeding behaviour of tau arises at high concentrations, with implications for the interpretation of high-dose intracranial challenge experiments and the possible contribution of seeded aggregation to human disease.}, language = {en}, number = {1}, urldate = {2021-03-25}, journal = {Acta Neuropathologica Communications}, author = {Miller, Lauren V. C. and Mukadam, Aamir S. and Durrant, Claire S. and Vaysburd, Marina J. and Katsinelos, Taxiarchis and Tuck, Benjamin J. and Sanford, Sophie and Sheppard, Olivia and Knox, Claire and Cheng, Shi and James, Leo C. and Coleman, Michael P. and McEwan, William A.}, month = dec, year = {2021}, keywords = {highlight, peer-reviewed}, pages = {41}, } @article{tanudjojo_phenotypic_2021, title = {Phenotypic manifestation of α-synuclein strains derived from {Parkinson}’s disease and multiple system atrophy in human dopaminergic neurons}, volume = {12}, issn = {2041-1723}, url = {http://www.nature.com/articles/s41467-021-23682-z}, doi = {10.1038/s41467-021-23682-z}, abstract = {Abstract α-Synuclein is critical in the pathogenesis of Parkinson’s disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson’s disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson’s disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons.}, language = {en}, number = {1}, urldate = {2021-06-22}, journal = {Nature Communications}, author = {Tanudjojo, Benedict and Shaikh, Samiha S. and Fenyi, Alexis and Bousset, Luc and Agarwal, Devika and Marsh, Jade and Zois, Christos and Heman-Ackah, Sabrina and Fischer, Roman and Sims, David and Melki, Ronald and Tofaris, George K.}, month = dec, year = {2021}, keywords = {highlight, peer-reviewed}, pages = {3817}, } @article{barth_microglial_2021, title = {Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures}, volume = {16}, issn = {1750-1326}, url = {https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-021-00471-2}, doi = {10.1186/s13024-021-00471-2}, abstract = {Abstract Background Proteopathic brain lesions are a hallmark of many age-related neurodegenerative diseases including synucleinopathies and develop at least a decade before the onset of clinical symptoms. Thus, understanding of the initiation and propagation of such lesions is key for developing therapeutics to delay or halt disease progression. Methods Alpha-synuclein (αS) inclusions were induced in long-term murine and human slice cultures by seeded aggregation. An αS seed-recognizing human antibody was tested for blocking seeding and/or spreading of the αS lesions. Release of neurofilament light chain (NfL) into the culture medium was assessed. Results To study initial stages of α-synucleinopathies, we induced αS inclusions in murine hippocampal slice cultures by seeded aggregation. Induction of αS inclusions in neurons was apparent as early as 1week post-seeding, followed by the occurrence of microglial inclusions in vicinity of the neuronal lesions at 2–3 weeks. The amount of αS inclusions was dependent on the type of αS seed and on the culture’s genetic background (wildtype vs A53T-αS genotype). Formation of αS inclusions could be monitored by neurofilament light chain protein release into the culture medium, a fluid biomarker of neurodegeneration commonly used in clinical settings. Local microinjection of αS seeds resulted in spreading of αS inclusions to neuronally connected hippocampal subregions, and seeding and spreading could be inhibited by an αS seed-recognizing human antibody. We then applied parameters of the murine cultures to surgical resection-derived adult human long-term neocortical slice cultures from 22 to 61-year-old donors. Similarly, in these human slice cultures, proof-of-principle induction of αS lesions was achieved at 1week post-seeding in combination with viral A53T-αS expressions. Conclusion The successful translation of these brain cultures from mouse to human with the first reported induction of human αS lesions in a true adult human brain environment underlines the potential of this model to study proteopathic lesions in intact mouse and now even aged human brain environments.}, language = {en}, number = {1}, urldate = {2021-09-07}, journal = {Molecular Neurodegeneration}, author = {Barth, Melanie and Bacioglu, Mehtap and Schwarz, Niklas and Novotny, Renata and Brandes, Janine and Welzer, Marc and Mazzitelli, Sonia and Häsler, Lisa M. and Schweighauser, Manuel and Wuttke, Thomas V. and Kronenberg-Versteeg, Deborah and Fog, Karina and Ambjørn, Malene and Alik, Ania and Melki, Ronald and Kahle, Philipp J. and Shimshek, Derya R. and Koch, Henner and Jucker, Mathias and Tanriöver, Gaye}, month = dec, year = {2021}, keywords = {highlight, peer-reviewed}, pages = {54}, } @article{barini_tau_2022, title = {Tau in the brain interstitial fluid is fragmented and seeding–competent}, volume = {109}, issn = {01974580}, url = {https://linkinghub.elsevier.com/retrieve/pii/S0197458021002943}, doi = {10.1016/j.neurobiolaging.2021.09.013}, language = {en}, urldate = {2022-02-17}, journal = {Neurobiology of Aging}, author = {Barini, Erica and Plotzky, Gudrun and Mordashova, Yulia and Hoppe, Jonas and Rodriguez-Correa, Esther and Julier, Sonja and LePrieult, Florie and Mairhofer, Ina and Mezler, Mario and Biesinger, Sandra and Cik, Miroslav and Meinhardt, Marcus W. and Ercan-Herbst, Ebru and Ehrnhoefer, Dagmar E. and Striebinger, Andreas and Bodie, Karen and Klein, Corinna and Gasparini, Laura and Schlegel, Kerstin}, month = jan, year = {2022}, pages = {64--77}, } @techreport{torre_murazabal_-synuclein_2020, type = {preprint}, title = {α-{Synuclein} strains influence multiple system atrophy via central and peripheral mechanisms}, url = {https://biorxiv.org/lookup/doi/10.1101/2020.10.16.342089}, abstract = {Abstract Multiple system atrophy (MSA) is a progressive neurodegenerative disease with prominent autonomic and motor features. Different disease subtypes are distinguished by their predominant parkinsonian or cerebellar signs. The pathognomonic feature of MSA is the presence of α-synuclein (αSyn) protein deposits in glial cells of the central and peripheral nervous system. It is unclear why MSA, that invariably presents with αSyn pathology, is clinically so heterogeneous, why it progresses at varying rates and how neuroinflammation affects disease progression. Recently, it was shown that different strains of αSyn can assemble in unique disease environments but also that a variety of strains might exist in the brain of MSA patients. We therefore investigated if different αSyn strains might influence MSA disease progression. To this aim, we injected two recombinant strains of αSyn in MSA transgenic mice and found that they significantly impact MSA disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of αSyn strains both in vitro and in vivo . By injecting αSyn strains in MSA mice we could more closely mimic a comprehensive MSA phenotype in an experimental setting. This study therefore shows that i) MSA phenotype is governed by both the αSyn strain nature and the host environment and ii) αSyn strains can directly trigger a detrimental immune response related to disease progression in MSA.}, language = {en}, urldate = {2022-02-17}, institution = {Neuroscience}, author = {Torre Murazabal, T. and Van der Perren, A. and Coens, A. and Barber Janer, A. and Camacho-Garcia, S. and Stefanova, N. and Melki, R. and Baekelandt, V. and Peelaerts, W.}, month = oct, year = {2020}, doi = {10.1101/2020.10.16.342089}, keywords = {preprint}, } @techreport{tuck_tau_2021, type = {preprint}, title = {Tau assemblies enter the cytosol in a cholesterol sensitive process essential to seeded aggregation}, url = {https://biorxiv.org/lookup/doi/10.1101/2021.06.21.449238}, abstract = {Abstract Accumulating evidence supports a prion-like mechanism in the spread of assembled tau in neurodegenerative diseases. Prion-like spread is proposed to require the transit of tau assemblies to the interior of neurons in order to seed aggregation of native, cytosolic tau. This process is poorly understood and remains largely hypothetical. Here, we develop sensitive techniques to quantify the cytosolic entry of tau in real-time. We find that tau does not promote its own entry but, rather, is wholly dependent on cellular machinery. We find that entry to the widely used reporter cell line HEK293 requires clathrin whereas entry to neurons does not. Cholesterol depletion or knockdown of cholesterol transport protein Niemann-Pick type C1 in neurons renders cells highly vulnerable to cytosolic entry and seeded aggregation. Our findings establish entry as the rate-limiting step in seeded aggregation and demonstrate that dysregulated cholesterol, a feature of several neurodegenerative diseases, potentiates tau aggregation. Graphical Abstract}, language = {en}, urldate = {2022-02-17}, institution = {Cell Biology}, author = {Tuck, Benjamin J. and Miller, Lauren V. C. and Wilson, Emma L. and Katsinelos, Taxiarchis and Cheng, Shi and Vaysburd, Marina and Knox, Claire and Tredgett, Lucy and Metzakopian, Emmanouil and James, Leo C. and McEwan, William A.}, month = jun, year = {2021}, doi = {10.1101/2021.06.21.449238}, keywords = {preprint}, } @techreport{burger_cryo-em_2021, type = {preprint}, title = {Cryo-{EM} structure of alpha-synuclein fibrils amplified by {PMCA} from {PD} and {MSA} patient brains}, url = {https://biorxiv.org/lookup/doi/10.1101/2021.07.08.451588}, abstract = {Abstract Synucleinopathies are neurodegenerative diseases related to the aggregation of the protein alpha-synuclein (aSyn). Among these diseases, Parkinson’s disease (PD) and multiple system atrophy (MSA) are most prevalent. aSyn can readily form different fibrillar polymorphs, if exposed to an air-water interface or by templating with pre-existing fibrils. We here report the structures of three fibrillar polymorphs that were obtained after seeding monomeric aSyn with PD and MSA patients brain homogenates using protein misfolding cyclic amplification (PMCA). Seeding with a control brain homogenate did not produce fibrils, and seeding with other in vitro generated fibrillar polymorphs as a control faithfully produced polymorphs of a different type. The here determined fibril structures from PD and MSA brain tissue represent new folds, which partly resemble that of previously reported in vitro generated fibrils from Y39 phosphorylated aSyn protein. The relevance of these fibrils for synucleinopathies in humans remains to be further investigated. Impact Statement Neurodegenerative diseases such as Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are suspected to be causatively related to the prion-like propagation of aggregates of the protein alpha-synuclein (aSyn). The fibril structures reported here were obtained after seeding from diseased human brain homogenate and differ from all previously published aSyn fibril arrangements. In case these fibrils would turn out to be the long sought causative agents of these diseases, their structures might lead to the development of therapeutic strategies to modify these diseases and to a better understanding of the mechanistic processes that lead to neurodegeneration and spreading of the diseases.}, language = {en}, urldate = {2022-02-17}, institution = {Neuroscience}, author = {Burger, Domenic and Fenyi, Alexis and Bousset, Luc and Stahlberg, Henning and Melki, Ronald}, month = jul, year = {2021}, doi = {10.1101/2021.07.08.451588}, keywords = {preprint}, } @article{tofaris_convergent_2018, title = {Convergent molecular defects underpin diverse neurodegenerative diseases}, volume = {89}, issn = {0022-3050, 1468-330X}, url = {https://jnnp.bmj.com/lookup/doi/10.1136/jnnp-2017-316988}, doi = {10.1136/jnnp-2017-316988}, abstract = {In our ageing population, neurodegenerative disorders carry an enormous personal, societal and economic burden. Although neurodegenerative diseases are often thought of as clinicopathological entities, increasing evidence suggests a considerable overlap in the molecular underpinnings of their pathogenesis. Such overlapping biological processes include the handling of misfolded proteins, defective organelle trafficking, RNA processing, synaptic health and neuroinflammation. Collectively but in different proportions, these biological processes in neurons or non-neuronal cells lead to regionally distinct patterns of neuronal vulnerability and progression of pathology that could explain the disease symptomology. With the advent of patient-derived cellular models and novel genetic manipulation tools, we are now able to interrogate this commonality despite the cellular complexity of the brain in order to develop novel therapeutic strategies to prevent or arrest neurodegeneration. Here, we describe broadly these concepts and their relevance across neurodegenerative diseases.}, language = {en}, number = {9}, urldate = {2022-02-14}, journal = {Journal of Neurology, Neurosurgery \& Psychiatry}, author = {Tofaris, George K and Buckley, Noel J}, month = sep, year = {2018}, keywords = {peer-reviewed}, pages = {962--969}, } @article{teil_targeting_2020, title = {Targeting α-{Synuclein} for {PD} {Therapeutics}: {A} {Pursuit} on {All} {Fronts}}, volume = {10}, issn = {2218-273X}, shorttitle = {Targeting α-{Synuclein} for {PD} {Therapeutics}}, url = {https://www.mdpi.com/2218-273X/10/3/391}, doi = {10.3390/biom10030391}, abstract = {Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.}, language = {en}, number = {3}, urldate = {2022-02-14}, journal = {Biomolecules}, author = {Teil, Margaux and Arotcarena, Marie-Laure and Faggiani, Emilie and Laferriere, Florent and Bezard, Erwan and Dehay, Benjamin}, month = mar, year = {2020}, keywords = {peer-reviewed}, pages = {391}, } @article{grozdanov_increased_2019, title = {Increased {Immune} {Activation} by {Pathologic} α‐{Synuclein} in {Parkinson}'s {Disease}}, volume = {86}, issn = {0364-5134, 1531-8249}, url = {https://onlinelibrary.wiley.com/doi/10.1002/ana.25557}, doi = {10.1002/ana.25557}, language = {en}, number = {4}, urldate = {2022-02-14}, journal = {Annals of Neurology}, author = {Grozdanov, Veselin and Bousset, Luc and Hoffmeister, Meike and Bliederhaeuser, Corinna and Meier, Christoph and Madiona, Karine and Pieri, Laura and Kiechle, Martin and McLean, Pamela J. and Kassubek, Jan and Behrends, Christian and Ludolph, Albert C. and Weishaupt, Jochen H. and Melki, Ronald and Danzer, Karin M.}, month = oct, year = {2019}, keywords = {peer-reviewed}, pages = {593--606}, } @article{mcmurray_synthesis_2021, title = {Synthesis and {Assessment} of {Novel} {Probes} for {Imaging} {Tau} {Pathology} in {Transgenic} {Mouse} and {Rat} {Models}}, volume = {12}, issn = {1948-7193, 1948-7193}, url = {https://pubs.acs.org/doi/10.1021/acschemneuro.0c00790}, doi = {10.1021/acschemneuro.0c00790}, language = {en}, number = {11}, urldate = {2022-01-03}, journal = {ACS Chemical Neuroscience}, author = {McMurray, Lindsay and Macdonald, Jennifer A. and Ramakrishnan, Nisha Kuzhuppilly and Zhao, Yanyan and Williamson, David W. and Tietz, Ole and Zhou, Xiaoyun and Kealey, Steven and Fagan, Steven G. and Smolek, Tomáš and Cubinkova, Veronika and Žilka, Norbert and Spillantini, Maria Grazia and Tolkovsky, Aviva M. and Goedert, Michel and Aigbirhio, Franklin I.}, month = jun, year = {2021}, keywords = {peer-reviewed}, pages = {1885--1893}, } @article{katsinelos_identification_2021, title = {Identification of cis-acting determinants mediating the unconventional secretion of tau}, volume = {11}, issn = {2045-2322}, url = {http://www.nature.com/articles/s41598-021-92433-3}, doi = {10.1038/s41598-021-92433-3}, abstract = {Abstract The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer’s disease. While recent findings suggest the involvement of unconventional secretory pathways driving tau into the extracellular space and mediating the propagation of the disease-associated pathology, many of the mechanistic details governing this process remain elusive. In the current study, we provide an in-depth characterization of the unconventional secretory pathway of tau and identify novel molecular determinants that are required for this process. Here, using Drosophila models of tauopathy, we correlate the hyperphosphorylation and aggregation state of tau with the disease-related neurotoxicity. These newly established systems recapitulate all the previously identified hallmarks of tau secretion, including the contribution of tau hyperphosphorylation as well as the requirement for PI(4,5)P 2 triggering the direct translocation of tau. Using a series of cellular assays, we demonstrate that both the sulfated proteoglycans on the cell surface and the correct orientation of the protein at the inner plasma membrane leaflet are critical determinants of this process. Finally, we identify two cysteine residues within the microtubule binding repeat domain as novel cis -elements that are important for both unconventional secretion and trans-cellular propagation of tau.}, language = {en}, number = {1}, urldate = {2021-06-22}, journal = {Scientific Reports}, author = {Katsinelos, Taxiarchis and McEwan, William A. and Jahn, Thomas R. and Nickel, Walter}, month = dec, year = {2021}, keywords = {peer-reviewed}, pages = {12946}, } @article{landureau_differential_2021, title = {The differential solvent exposure of {N}-terminal residues provides ‘fingerprints’ of alpha-synuclein fibrillar polymorphs}, issn = {00219258}, url = {https://linkinghub.elsevier.com/retrieve/pii/S0021925821005263}, doi = {10.1016/j.jbc.2021.100737}, language = {en}, urldate = {2021-05-05}, journal = {Journal of Biological Chemistry}, author = {Landureau, Maud and Redeker, Virginie and Bellande, Tracy and Eyquem, Stéphanie and Melki, Ronald}, month = apr, year = {2021}, keywords = {peer-reviewed}, pages = {100737}, } @article{zoehner_reduced_2019, title = {Reduced serum immunoglobulin {G} concentrations in multiple sclerosis: prevalence and association with disease-modifying therapy and disease course}, volume = {12}, issn = {1756-2864, 1756-2864}, shorttitle = {Reduced serum immunoglobulin {G} concentrations in multiple sclerosis}, url = {http://journals.sagepub.com/doi/10.1177/1756286419878340}, doi = {10.1177/1756286419878340}, abstract = {Background: In multiple sclerosis (MS), the frequency of hypogammaglobulinemia is unknown. We aimed to evaluate the frequency of reduced immunoglobulin (Ig) concentrations and its association with immunotherapy and disease course in two independent MS cohorts. Methods: In our retrospective cross-sectional study, MS patients and control patients with head or neck pain from Bern University Hospital (Bern, Switzerland) and Eginition University Hospital (Athens, Greece) were included. The lower limits of normal (LLN) for serum Ig concentration were IgG {\textless} 700 mg/dl, IgM {\textless} 40 mg/dl, and IgA {\textless} 70 mg/dl. Mann–Whitney U test, analysis of variance test, and multiple linear regression analysis were employed. Results: In total, 327 MS patients were retrospectively identified (Bern/Athens: n = 226/101). Serum IgG concentrations were frequently under LLN in both MS cohorts (Bern/Athens: 15.5\%/14.9\%), even when considering only untreated patients (Bern/Athens: 7.9\%/8.6\%). MS patients ( n = 327) were significantly more likely to have IgG concentrations below LLN and below 600 mg/dl in comparison with controls ( n = 58) ( p = 0.015 and 0.047, respectively). Between both patient groups, no significant differences were found in frequencies of IgA and IgM concentrations under LLN [ n (MS patients/controls): IgA 203/30, IgM 224/24]. Independently of age, secondary progressive MS patients had lower IgG concentrations than relapsing–remitting and primary progressive patients (both: p ⩽ 0.01). After adjusting for sex, age, and disease course, IgG concentrations were lower in patients treated with rituximab ( p = 0.001; n = 42/327), intravenous corticosteroids ( p {\textless} 0.001; n = 16/327), natalizumab ( p {\textless} 0.001; n = 48/327), and fingolimod ( p = 0.003; n = 6/327). Conclusion: Our study demonstrated high prevalence rates of reduced serum IgG concentrations in MS patients with and without disease-modifying treatments. The significance of lower IgG concentrations at the levels noted is unclear considering that infections or interference with antibody production generally occur when IgG levels are much lower, at or below 400 mg/dl. However, the information is useful to monitor IgG levels especially with anti-B-cell therapies and consider IgG substitution when levels drop below 400 mg/dl.}, language = {en}, urldate = {2021-02-24}, journal = {Therapeutic Advances in Neurological Disorders}, author = {Zoehner, Greta and Miclea, Andrei and Salmen, Anke and Kamber, Nicole and Diem, Lara and Friedli, Christoph and Bagnoud, Maud and Ahmadi, Farhad and Briner, Myriam and Sédille-Mostafaie, Nazanin and Kilidireas, Constantinos and Stefanis, Leonidas and Chan, Andrew and Hoepner, Robert and Evangelopoulos, Maria Eleftheria}, month = jan, year = {2019}, keywords = {peer-reviewed}, pages = {175628641987834}, } @article{nachman_disassembly_2020, title = {Disassembly of {Tau} fibrils by the human {Hsp70} disaggregation machinery generates small seeding-competent species}, volume = {295}, issn = {00219258}, url = {https://linkinghub.elsevier.com/retrieve/pii/S0021925817489836}, doi = {10.1074/jbc.RA120.013478}, language = {en}, number = {28}, urldate = {2021-02-24}, journal = {Journal of Biological Chemistry}, author = {Nachman, Eliana and Wentink, Anne S. and Madiona, Karine and Bousset, Luc and Katsinelos, Taxiarchis and Allinson, Kieren and Kampinga, Harm and McEwan, William A. and Jahn, Thomas R. and Melki, Ronald and Mogk, Axel and Bukau, Bernd and Nussbaum-Krammer, Carmen}, month = jul, year = {2020}, keywords = {peer-reviewed}, pages = {9676--9690}, } @article{bendifallah_interaction_2020, title = {Interaction of the chaperones alpha {B}-crystallin and {CHIP} with fibrillar alpha-synuclein: {Effects} on internalization by cells and identification of interacting interfaces}, volume = {527}, issn = {0006291X}, shorttitle = {Interaction of the chaperones alpha {B}-crystallin and {CHIP} with fibrillar alpha-synuclein}, url = {https://linkinghub.elsevier.com/retrieve/pii/S0006291X20308172}, doi = {10.1016/j.bbrc.2020.04.091}, language = {en}, number = {3}, urldate = {2021-02-24}, journal = {Biochemical and Biophysical Research Communications}, author = {Bendifallah, Maya and Redeker, Virginie and Monsellier, Elodie and Bousset, Luc and Bellande, Tracy and Melki, Ronald}, month = jun, year = {2020}, keywords = {peer-reviewed}, pages = {760--769}, } @article{russ_tnf-_2021, title = {{TNF}-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration}, volume = {34}, issn = {22111247}, url = {https://linkinghub.elsevier.com/retrieve/pii/S2211124721002096}, doi = {10.1016/j.celrep.2021.108895}, language = {en}, number = {12}, urldate = {2021-03-26}, journal = {Cell Reports}, author = {Russ, Kaspar and Teku, Gabriel and Bousset, Luc and Redeker, Virginie and Piel, Sara and Savchenko, Ekaterina and Pomeshchik, Yuriy and Savistchenko, Jimmy and Stummann, Tina C. and Azevedo, Carla and Collin, Anna and Goldwurm, Stefano and Fog, Karina and Elmer, Eskil and Vihinen, Mauno and Melki, Ronald and Roybon, Laurent}, month = mar, year = {2021}, keywords = {peer-reviewed}, pages = {108895}, } @article{falcon_tau_2018, title = {Tau filaments from multiple cases of sporadic and inherited {Alzheimer}’s disease adopt a common fold}, volume = {136}, issn = {0001-6322, 1432-0533}, url = {http://link.springer.com/10.1007/s00401-018-1914-z}, doi = {10.1007/s00401-018-1914-z}, language = {en}, number = {5}, urldate = {2021-03-26}, journal = {Acta Neuropathologica}, author = {Falcon, Benjamin and Zhang, Wenjuan and Schweighauser, Manuel and Murzin, Alexey G. and Vidal, Ruben and Garringer, Holly J. and Ghetti, Bernardino and Scheres, Sjors H. W. and Goedert, Michel}, month = nov, year = {2018}, keywords = {peer-reviewed}, pages = {699--708}, } @article{kundel_measurement_2018, title = {Measurement of {Tau} {Filament} {Fragmentation} {Provides} {Insights} into {Prion}-like {Spreading}}, volume = {9}, issn = {1948-7193, 1948-7193}, url = {https://pubs.acs.org/doi/10.1021/acschemneuro.8b00094}, doi = {10.1021/acschemneuro.8b00094}, language = {en}, number = {6}, urldate = {2021-03-26}, journal = {ACS Chemical Neuroscience}, author = {Kundel, Franziska and Hong, Liu and Falcon, Benjamin and McEwan, William A. and Michaels, Thomas C. T. and Meisl, Georg and Esteras, Noemi and Abramov, Andrey Y. and Knowles, Tuomas J. P. and Goedert, Michel and Klenerman, David}, month = jun, year = {2018}, keywords = {peer-reviewed}, pages = {1276--1282}, } @article{bieri_lrrk2_2019, title = {{LRRK2} modifies α-syn pathology and spread in mouse models and human neurons}, volume = {137}, issn = {0001-6322, 1432-0533}, url = {http://link.springer.com/10.1007/s00401-019-01995-0}, doi = {10.1007/s00401-019-01995-0}, language = {en}, number = {6}, urldate = {2021-03-26}, journal = {Acta Neuropathologica}, author = {Bieri, Gregor and Brahic, Michel and Bousset, Luc and Couthouis, Julien and Kramer, Nicholas J. and Ma, Rosanna and Nakayama, Lisa and Monbureau, Marie and Defensor, Erwin and Schüle, Birgitt and Shamloo, Mehrdad and Melki, Ronald and Gitler, Aaron D.}, month = jun, year = {2019}, keywords = {peer-reviewed}, pages = {961--980}, } @article{stefanis_how_2019, title = {How is alpha‐synuclein cleared from the cell?}, volume = {150}, issn = {0022-3042, 1471-4159}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/jnc.14704}, doi = {10.1111/jnc.14704}, language = {en}, number = {5}, urldate = {2020-11-20}, journal = {Journal of Neurochemistry}, author = {Stefanis, Leonidas and Emmanouilidou, Evangelia and Pantazopoulou, Marina and Kirik, Deniz and Vekrellis, Kostas and Tofaris, George K.}, month = sep, year = {2019}, keywords = {peer-reviewed}, pages = {577--590}, } @article{katsinelos_role_2019, title = {The {Role} of {Antibodies} and {Their} {Receptors} in {Protection} {Against} {Ordered} {Protein} {Assembly} in {Neurodegeneration}}, volume = {10}, issn = {1664-3224}, url = {https://www.frontiersin.org/article/10.3389/fimmu.2019.01139/full}, doi = {10.3389/fimmu.2019.01139}, urldate = {2020-11-20}, journal = {Frontiers in Immunology}, author = {Katsinelos, Taxiarchis and Tuck, Benjamin J. and Mukadam, Aamir S. and McEwan, William A.}, month = may, year = {2019}, keywords = {peer-reviewed}, pages = {1139}, } @article{courte_expression_2020, title = {The expression level of alpha-synuclein in different neuronal populations is the primary determinant of its prion-like seeding}, volume = {10}, issn = {2045-2322}, url = {http://www.nature.com/articles/s41598-020-61757-x}, doi = {10.1038/s41598-020-61757-x}, language = {en}, number = {1}, urldate = {2020-11-20}, journal = {Scientific Reports}, author = {Courte, Josquin and Bousset, Luc and Boxberg, Ysander Von and Villard, Catherine and Melki, Ronald and Peyrin, Jean-Michel}, month = dec, year = {2020}, keywords = {peer-reviewed}, pages = {4895}, } @article{chabrat_pharmacological_2019, title = {Pharmacological {Transdifferentiation} of {Human} {Nasal} {Olfactory} {Stem} {Cells} into {Dopaminergic} {Neurons}}, volume = {2019}, issn = {1687-966X, 1687-9678}, url = {https://www.hindawi.com/journals/sci/2019/2945435/}, doi = {10.1155/2019/2945435}, abstract = {The discovery of novel drugs for neurodegenerative diseases has been a real challenge over the last decades. The development of patient- and/or disease-specific in vitro models represents a powerful strategy for the development and validation of lead candidates in preclinical settings. The implementation of a reliable platform modeling dopaminergic neurons will be an asset in the study of dopamine-associated pathologies such as Parkinson’s disease. Disease models based on cell reprogramming strategies, using either human-induced pluripotent stem cells or transcription factor-mediated transdifferentiation, are among the most investigated strategies. However, multipotent adult stem cells remain of high interest to devise direct conversion protocols and establish in vitro models that could bypass certain limitations associated with reprogramming strategies. Here, we report the development of a six-step chemically defined protocol that drives the transdifferentiation of human nasal olfactory stem cells into dopaminergic neurons. Morphological changes were progressively accompanied by modifications matching transcript and protein dopaminergic signatures such as LIM homeobox transcription factor 1 alpha (LMX1A), LMX1B, and tyrosine hydroxylase (TH) expression, within 42 days of differentiation. Phenotypic changes were confirmed by the production of dopamine from differentiated neurons. This new strategy paves the way to develop more disease-relevant models by establishing reprogramming-free patient-specific dopaminergic cell models for drug screening and/or target validation for neurodegenerative diseases.}, language = {en}, urldate = {2020-11-20}, journal = {Stem Cells International}, author = {Chabrat, Audrey and Lacassagne, Emmanuelle and Billiras, Rodolphe and Landron, Sophie and Pontisso-Mahout, Amélie and Darville, Hélène and Dupront, Alain and Coge, Francis and Schenker, Esther and Piwnica, David and Nivet, Emmanuel and Féron, François and Mannoury la Cour, Clotilde}, month = may, year = {2019}, keywords = {peer-reviewed}, pages = {1--15}, } @article{alam_synuclein_2019, title = {α‐synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities}, volume = {150}, issn = {0022-3042, 1471-4159}, shorttitle = {α‐synuclein oligomers and fibrils}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/jnc.14808}, doi = {10.1111/jnc.14808}, language = {en}, number = {5}, urldate = {2020-11-20}, journal = {Journal of Neurochemistry}, author = {Alam, Parvez and Bousset, Luc and Melki, Ronald and Otzen, Daniel E.}, month = sep, year = {2019}, keywords = {peer-reviewed}, pages = {522--534}, } @article{vasili_spreading_2019, title = {Spreading of α-{Synuclein} and {Tau}: {A} {Systematic} {Comparison} of the {Mechanisms} {Involved}}, volume = {12}, issn = {1662-5099}, shorttitle = {Spreading of α-{Synuclein} and {Tau}}, url = {https://www.frontiersin.org/article/10.3389/fnmol.2019.00107/full}, doi = {10.3389/fnmol.2019.00107}, urldate = {2020-11-20}, journal = {Frontiers in Molecular Neuroscience}, author = {Vasili, Eftychia and Dominguez-Meijide, Antonio and Outeiro, Tiago Fleming}, month = apr, year = {2019}, keywords = {peer-reviewed}, pages = {107}, } @article{rey_-synuclein_2019, title = {α-{Synuclein} conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb}, volume = {7}, issn = {2051-5960}, url = {https://doi.org/10.1186/s40478-019-0859-3}, doi = {10.1186/s40478-019-0859-3}, abstract = {Alpha-synuclein inclusions, the hallmarks of synucleinopathies, are suggested to spread along neuronal connections in a stereotypical pattern in the brains of patients. Ample evidence now supports that pathological forms of alpha-synuclein propagate in cell culture models and in vivo in a prion-like manner. However, it is still not known why the same pathological protein targets different cell populations, propagates with different kinetics and leads to a variety of diseases (synucleinopathies) with distinct clinical features. The aggregation of the protein alpha-synuclein yields different conformational polymorphs called strains. These strains exhibit distinct biochemical, physical and structural features they are able to imprint to newly recruited alpha-synuclein. This had led to the view that the clinical heterogeneity observed in synucleinopathies might be due to distinct pathological alpha-synuclein strains.}, number = {1}, urldate = {2020-01-14}, journal = {Acta Neuropathologica Communications}, author = {Rey, Nolwen L. and Bousset, Luc and George, Sonia and Madaj, Zachary and Meyerdirk, Lindsay and Schulz, Emily and Steiner, Jennifer A. and Melki, Ronald and Brundin, Patrik}, month = dec, year = {2019}, keywords = {peer-reviewed}, pages = {221}, } @article{gribaudo_propagation_2019, title = {Propagation of α-{Synuclein} {Strains} within {Human} {Reconstructed} {Neuronal} {Network}}, volume = {0}, issn = {2213-6711}, url = {https://www.cell.com/stem-cell-reports/abstract/S2213-6711(18)30526-5}, doi = {10.1016/j.stemcr.2018.12.007}, language = {English}, number = {0}, urldate = {2019-01-11}, journal = {Stem Cell Reports}, author = {Gribaudo, Simona and Tixador, Philippe and Bousset, Luc and Fenyi, Alexis and Lino, Patricia and Melki, Ronald and Peyrin, Jean-Michel and Perrier, Anselme L.}, month = jan, year = {2019}, keywords = {Lewy body, Parkinson's disease, human cortical neuron, human pluripotent stem cells, microfluidic, neuronal dysfunction, nucleation, peer-reviewed, prion-like, synuclein}, } @article{goedert_tau_2018, title = {Tau {Filaments} and the {Development} of {Positron} {Emission} {Tomography} {Tracers}}, volume = {9}, issn = {1664-2295}, url = {http://journal.frontiersin.org/article/10.3389/fneur.2018.00070/full}, doi = {10.3389/fneur.2018.00070}, urldate = {2018-11-26}, journal = {Frontiers in Neurology}, author = {Goedert, Michel and Yamaguchi, Yoshiki and Mishra, Sushil K. and Higuchi, Makoto and Sahara, Naruhiko}, month = feb, year = {2018}, keywords = {peer-reviewed}, } @article{spillantini_neurodegeneration_2018, title = {Neurodegeneration and the ordered assembly of α-synuclein}, volume = {373}, issn = {0302-766X, 1432-0878}, url = {http://link.springer.com/10.1007/s00441-017-2706-9}, doi = {10.1007/s00441-017-2706-9}, language = {en}, number = {1}, urldate = {2018-11-26}, journal = {Cell and Tissue Research}, author = {Spillantini, Maria Grazia and Goedert, Michel}, month = jul, year = {2018}, keywords = {peer-reviewed}, pages = {137--148}, } @article{hopfner_allogeneic_2021, title = {Allogeneic {BK} {Virus}-{Specific} {T}-{Cell} {Treatment} in 2 {Patients} {With} {Progressive} {Multifocal} {Leukoencephalopathy}}, volume = {8}, issn = {2332-7812}, url = {http://nn.neurology.org/lookup/doi/10.1212/NXI.0000000000001020}, doi = {10.1212/NXI.0000000000001020}, abstract = {Objective Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating opportunistic infection of the brain caused by the ubiquitously distributed JC polyomavirus. There are no established treatment options to stop or slow down disease progression. In 2018, a case series of 3 patients suggested the efficacy of allogeneic BK virus-specific T-cell (BKV-CTL) transplantation. Methods Two patients, a bilaterally lung transplanted patient on continuous immunosuppressive medication since 17 years and a patient with dermatomyositis treated with glucocorticosteroids, developed definite PML according to AAN diagnostic criteria. We transplanted both patients with allogeneic BKV-CTL from partially human leukocyte antigen (HLA) compatible donors. Donor T cells had directly been produced from leukapheresis by the CliniMACS IFN-γ cytokine capture system. In contrast to the previous series, we identified suitable donors by HLA typing in a preexamined registry and administered 1 log level less cells. Results Both patients' symptoms improved significantly within weeks. During the follow-up, a decrease in viral load in the CSF and a regression of the brain MRI changes occurred. The transfer seemed to induce endogenous BK and JC virus-specific T cells in the host. Conclusions We demonstrate that this optimized allogeneic BKV-CTL treatment paradigm represents a promising, innovative therapeutic option for PML and should be investigated in larger, controlled clinical trials. Classification of Evidence This study provides Class IV evidence that for patients with PML, allogeneic transplant of BKV-CTL improved symptoms, reduced MRI changes, and decreased viral load.}, language = {en}, number = {4}, urldate = {2022-02-14}, journal = {Neurology - Neuroimmunology Neuroinflammation}, author = {Hopfner, Franziska and Möhn, Nora and Eiz-Vesper, Britta and Maecker-Kolhoff, Britta and Gottlieb, Jens and Blasczyk, Rainer and Mahmoudi, Nima and Pars, Kaweh and Adams, Ortwin and Stangel, Martin and Wattjes, Mike P. and Höglinger, Günter and Skripuletz, Thomas}, month = jul, year = {2021}, keywords = {peer-reviewed}, pages = {e1020}, } @article{tofaris_critical_2017, title = {A {Critical} {Assessment} of {Exosomes} in the {Pathogenesis} and {Stratification} of {Parkinson}’s {Disease}}, volume = {7}, issn = {18777171, 1877718X}, url = {http://www.medra.org/servlet/aliasResolver?alias=iospress&doi=10.3233/JPD-171176}, doi = {10.3233/JPD-171176}, number = {4}, urldate = {2018-11-26}, journal = {Journal of Parkinson's Disease}, author = {Tofaris, George K.}, month = nov, year = {2017}, keywords = {peer-reviewed}, pages = {569--576}, }