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One of the principal neuropathological features of Parkinson’s disease and dementia is the formation of abnormal clumps of a sticky protein called alpha-synuclein. These protein clumps build up in the brain causing the death of nerve cells, especially the dopamine producing neurons that control movement. The progressive incorporation of alpha-synuclein into protein clumps is thought to involve a seeding-like mechanism.

This area of research is challenging because there are no models that faithfully replicate the sequence of events in neuronal tissue that leads to Parkinson’s disease. We need such models in order to understand how aggregated alpha-synuclein kills nerve cells, and to inform disease-modifying strategies.

Dr Tofaris and his team 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.

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