A new study has revealed a key mechanism by which a protein associated with Parkinson’s disease damages neurons (brain cells) by blocking a vital cellular gateway. The findings help to explain how the disease begins and highlights a potential new target for treatment.
Parkinson’s disease, which affects more than 10 million people worldwide, is characterised by the build-up of abnormal clumps of the protein alpha-synuclein inside brain cells, but scientists have long struggled to understand exactly how these toxic forms of the protein cause neurons to malfunction and eventually die.
The study, published in Nature Communications, was supported by the NIHR Biomedical Research Centre: Oxford.
The researchers from the University of Oxford’s Nuffield Department of Clinical Neurosciences (NDCN) combined advanced molecular analyses of human stem cell models of Parkinson’s disease with studies of post-mortem brain tissue from people with Parkinson’s disease to investigate the earliest stages of the disease process.
They found that toxic forms of alpha-synuclein bind to a protein called Sec61A, blocking part of a molecular ‘gateway’ that helps newly made proteins enter the cell’s protein-processing centre, known as the endoplasmic reticulum.
Blocking this gateway did not activate the classical cellular stress response normally associated with damage to the endoplasmic reticulum. Instead, neurons activated an alternative quality-control pathway, suggesting that this represents a previously unrecognised early event in Parkinson’s disease.
Professor George Tofaris (pictured left), senior author of the study, explained: “Our work shows that toxic alpha-synuclein blocks one of the cell’s most fundamental protein delivery systems. This provides a unifying explanation for why many different genetic risk factors for Parkinson’s disease ultimately disrupt the same cellular processes.
“Perhaps the most encouraging finding was that we could reverse these defects in human neurons by boosting the cell’s own protein-clearance machinery. Although much more work is needed before this approach can be tested in patients, our findings provide a rationale for exploring this strategy as an early treatment for Parkinson’s disease.”