RESEARCH HIGHLIGHT - Classification of human tauopathies based on tau filament folds

This paper from the LMB team presents Cryo-EM analysis of tau filament structures from a range of neurodegenerative diseases that suggests a new method for characterising tauopathies

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RESEARCH HIGHLIGHT - Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures

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. This work carried out by the DZNE team allows to better understand the initiation and propagation of such lesions, a key knowledge for developing therapeutics to delay or halt disease progression.

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RESEARCH HIGHLIGHT – A stem cell-based model offers new insights into the mechanisms of neuronal loss in Parkinson’s disease

IMPRiND partners UOXF and CNRS have now come up with a working laboratory model. They used induced pluripotent stem cells (iPSC) derived from both healthy subjects and patients with the alpha-synuclein gene defects to generate human dopaminergic neurons that are primarily affected in Parkinson’s disease. They found a way of ‘amplifying’ in a fairly pure form, the main constituent, called fibril, of alpha-synuclein clumps directly from post-mortem Parkinson’s brains. When they added these brain-derived fibrils onto the human dopaminergic neurons, they successfully triggered the aggregation of alpha-synuclein inside the cells and observed progressive neuronal loss.

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RESEARCH HIGHLIGHT - New insights into the behaviour of tau seeded aggregation in neural tissue

A better understanding of the spreading of the aggregates of protein tau is key to be able to interfere with the progression of neurodegenerative disorders such as Alzheimer’s disease. The LMB team developed a new model of tau pathology that allowed them to follow this process and to get new insights into the behaviour of tau seeded aggregation in neural tissue.

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RESEARCH HIGHLIGHT - Seeding Propensity and Characteristics of Pathogenic αSyn Assemblies in Formalin-Fixed Human Tissue

This study of α-synuclein’s (α-syn) seeding activity in tissue from the brain and enteric nervous system by the IMPRiND team CNRS suggests that different strains exist within the brain of individuals suffering from PD.

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RESEARCH HIGHLIGHT - Differential Membrane Binding and Seeding of Distinct α-Synuclein Fibrillar Polymorphs

The aggregation of the protein α-synuclein (α-syn) leads to different synucleinopathies. IMPRIND Partner CNRS showed that structurally distinct fibrillar

α-syn polymorphs trigger either Parkinson’s disease or multiple system atrophy hallmarks in vivo.

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RESEARCH HIGHLIGHT – When stealth α-synuclein fibrils take over

In this study published in Sciences Advances, the UBx team discovered that during fibril formation in a physiological salt solution, α-syn can actually randomly adopt several amyloid folds, but several of the fibril polymorphs that emerge, were, up to now, left unnoticed. This discovery is of particular importance for the research on neurodegenerative synucleinopathies, a condition directly associated with several neurodegenerative diseases, including Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA).

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RESEARCH HIGHLIGHT – Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

The OMG-GOE team developed a simple laboratory model system to investigate the mechanisms leading to the aggregation and propagation of specific proteins, directly linked with two common neurodegenerative disorders, Parkinson's disease (PD) and Alzheimer's disease (AD). In this study published in Nature in July 2020, they assessed the effects of molecules on the aggregation and internalisation of tau and α-syn and identified some that can decrease α-syn and/or tau aggregation. Establishing the effects of small molecules with different chemical properties on the aggregation and spreading of α-syn and tau will be important for the development of novel therapeutic strategies.

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RESEARCH HIGHLIGHT - Distinct alpha-Synuclein species induced by seeding are selectively cleared by the Lysosome or the Proteasome in neuronally differentiated SH-SY5Y cells

The collaboration between the IMPRiND teams BRFAA and CNRS resulted into new and important insights into the biology of α-Syn aggregation and turnover.

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RESEARCH HIGHLIGHT - Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions

The aim of this work by the DZNE team was to study α-synuclein (α-syn) conformers among different transgenic (TG) mouse models of α-synucleinopathies.

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RESEARCH HIGHLIGHT - Structures of alpha-synuclein filaments from multiple system atrophy

Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are synucleinopathies. They are characterized by the presence of abundant filamentous inclusions of alpha-synuclein (α-syn) in nerve cells and glial cells, in the form of Lewy bodies and Papp-Lantos bodies. The relevance of inclusion formation was established when gene dosage and missense mutations in SNCA, the α-syn gene, were shown to cause inherited forms of PD and DLB, with abundant Lewy pathology. In diseases with Lewy pathology, α-syn inclusions are found mostly in nerve cells, whereas they predominate in glial cells in MSA. Several indirect lines of evidence have suggested that the inclusions in diseases with Lewy pathology and those in MSA are different conformers of assembled α-syn.

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RESEARCH HIGHLIGHT - The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson’s disease, multiple system atrophy and dementia with Lewy bodies

IMPRIND Partner CNRS establishes a method where seeds from frozen brain tissues can seed the aggregation of pure alpha-synuclein.

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RESEARCH HIGHLIGHT - A novel tau fold in the neurodegenerative disease corticobasal degeneration

New structures of tau filaments from corticobasal degeneration are the first to be revealed for the most common category of tauopathies after Alzheimer’s disease

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RESEARCH HIGHLIGHT - Journey to the centre of pathogenic alpha-synuclein aggregate

The protein alpha-synuclein aggregates are constituents of Lewy bodies, a histological hallmark of the synuceinopathies Parkinson's disease, Lewy body dementia and multiple system atrophy.

Elucidating the forms alpha-synuclein molecules adopt upon staking within aggregates is key for the design of ligands targeting those aggregates. Such ligands could attach along or at the ends of the resulting fibrils and affect their surface properties or their ability to elongate and thus limit the pathological processes involved in synucleinopathies.

Partner CNRS within a collaborative study with experts in Cryo-Electron microscopy recently determined a new structure for alpha-synuclein fibrils, down to an atomic level. Those fibrils, when injected into rodent models, cause the development of symptoms characteristic of Parkinson's disease.

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RESEARCH HIGHLIGHT - Detection of alpha-synuclein aggregates in gastrointestinal biopsies by protein misfolding cyclic amplification

The observation that alpha-synuclein (α-syn) aggregates are also found in the enteric nervous system has prompted IMPRIND Partner CNRS to develop a diagnostic procedure based on the detection of pathological α-syn in gastrointestinal biopsies.

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This project receives funding from the Innovative Medicines Initiative 2 Joint Undertaking ( under grant agreement No 116060. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 17.00038.

The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies.

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