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Tofaris group
Parkinson's disease affects more than 10 million people worldwide. The disease 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.
Researchers from the Tofaris lab, part of the Nuffield Department of Clinical Neurosciences and based in the Kavli Institute for Nanoscience Discovery 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.
The researchers 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, known as UFMylation, suggesting that this represents a previously unrecognised early event in Parkinson's disease.
This gateway is essential for ensuring that proteins are correctly delivered to the cellular compartments where they perform their functions. When this gateway became blocked, several important proteins failed to reach the cell's recycling centres, known as lysosomes.
Without these proteins, lysosomes became less effective at clearing unwanted proteins and other cellular waste. As the recycling system failed, neurons released increased amounts of alpha-synuclein in tiny membrane-bound particles known as extracellular vesicles.
Previous work from the group showed that these vesicles can be detected in the bloodstream and could serve as biomarkers of early Parkinson's disease.
Importantly, several of the proteins affected by this blockage are encoded by genes already known to influence someone’s risk of developing Parkinson's disease. This suggests that disruption of this single protein delivery pathway may provide a common explanation for how diverse genetic risk factors ultimately contribute to Parkinson’s disease.
The team also showed that reducing levels of toxic alpha-synuclein restored normal protein transport inside cells.
This was achieved either by lowering alpha-synuclein production using CRISPR interference or by enhancing the activity of the proteasome, the cell's main protein clearance system, using drugs already approved for other medical conditions.
Professor George Tofaris, senior author of the study, explained that "For many years we have known that alpha-synuclein accumulates in Parkinson's disease, but we have not understood exactly how it causes such widespread damage inside neurons.
"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.”
Professor Tofaris added: "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."
The full paper α-Synuclein blocks endoplasmic reticulum co-translational protein 1 translocation early in Parkinson’s disease can be read in Nature Communications