Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. 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

Viewing self-harm images on the internet and in social media usually causes harm, according to new review

Clinical researchers have reviewed the international research evidence regarding the impact of viewing images of self-harm on the internet and in social media.

Can humans hibernate?

Illuminating new TEDx Talk from Professor of Sleep Physiology Vladyslav Vyazovskiy

European Platform for Neurodegenerative Diseases launches repository of cohorts for researchers

The new Cohort Catalogue will facilitate discovery of over 60 neurodegeneration research cohorts from 17 countries across Europe

New insights into chemogenetic designer drugs to enhance our study of behaviour

A collaborative team of researchers in DPAG and Pharmacology led by Dr Lukas Krone have uncovered striking new data demonstrating that two widely used designer drugs used to turn populations of neurons on and off in the brain cause unexpected effects on sleep. These results demonstrate a critical need to improve chemogenetic approaches in behavioural studies.

Researchers win UK Dementia Research Institute Grand Challenge Award to identify early signs of Alzheimer's

The MRC Brain Network Dynamics Unit has received funding for a multi-year research partnership designed to advance the understanding of early changes to the operations of brain circuits in Alzheimer's disease.

Ensuring LGBTQI+ people are treated fairly in mental health data

Andrey Kormilitzin outlines a new participatory study aimed at improving AI to take account of LGBTQI+ people so that their needs are better met by mental health services.