Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Similar stories

NICE recommends offering app-based treatment for people with insomnia instead of sleeping pills

Hundreds of thousands of people suffering from insomnia who would usually be prescribed sleeping pills could be offered an app-based treatment programme instead, NICE has said.

Developmental dynamics of the neural crest–mesenchymal axis in creating the thymic microenvironment

A new paper from researchers at the Department of Paediatrics and the Nuffield Department of Clinical Neurosciences has shown that fibroblasts in the thymus, often considered simply as dull “structural” cells, are much more complex than previously thought.

How to use the science of the body clock to improve our sleep and health

Professor Russell Foster has written a new book about circadian neuroscience which is published by Penguin this week. This book review by Jacqueline Pumphrey was first published on the University of Oxford website.

Funding awarded for autoimmune disease research

Dr Kate Attfield awarded project funding by Connect Immune Research and The Lorna and Yuti Chernajovsky Biomedical Research Foundation.