The collaboration between IMPRiND partners UOXF and CNRS led to a strong working laboratory model. They used induced pluripotent stem cells (iPSC) derived from both healthy subjects and patients with the α-Syn 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 α-Syn 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 α-Syn inside the cells and observed progressive neuronal loss.
Reporting in Nature Communications, this model was used to show that the two main determinants of neuronal death are: (a) the abundance of α-Syn inside nerve cells, and (b) the structure it acquires when it assembles into aggregates. By tracking the molecular interactions of the toxic forms of α-Syn aggregates in living cells, they discovered that they cause damage partly by evading the protective effects of PARK7/DJ-1. Deletion of DJ-1 in iPSC-derived neurons increased α-Syn aggregation and neuronal death. This could explain why loss of function mutations in DJ-1 in patients causes Parkinson’s disease.
These findings are important because they provide a fully human model to decipher how α-Syn clumps cause nerve damage. This model will allow us to start targeting the toxic effects of α-Syn clumps with novel therapeutics.
Fibrils amplified from post-mortem Parkinson’s brain were used to trigger endogenous α-Syn aggregation and death in patient-derived neurons.
This project receives funding from the Innovative Medicines Initiative 2 Joint Undertaking (www.imi.europa.eu) 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.