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

Project Coordinator of the Innovative Medicines Initiative’s IMPRiND project Dr Tofaris and his team at UOXF in collaboration with Ronald Melki (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.

Reporting in Nature Communications, Tanudjojo et al. used this model to show that the two main determinants of neuronal death are: (a) the abundance of alpha-synuclein inside nerve cells, and (b) the structure it acquires when it assembles into aggregates. By tracking the molecular interactions of the toxic forms of alpha-synuclein 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 alpha-synuclein 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 alpha-synuclein clumps cause nerve damage. This model will allow us to start targeting the toxic effects of alpha-synuclein clumps with novel therapeutics.

This article was originally posted on: https://imprind.org/news/?post_id=67&title=research-highlight-%E2%80%93-a-stem-cell-based-model-offers-new-insights-into-the-mechanisms-of-neuronal-loss-in-parkinson%E2%80%99s-disease