Parkinson's-linked α-synuclein blocks protein transport in neurons, disrupting cells' waste recycling

Parkinson's disease, a condition affecting over 10 million individuals globally, is characterized by the accumulation of abnormal alpha-synuclein protein clumps within brain cells. Scientists have yet to fully comprehend how these toxic protein forms lead to neuronal malfunction and eventual cell death. Researchers from the Tofaris lab, part of the Nuffield Department of Clinical Neurosciences, have utilized advanced molecular analyses of human stem cell models, combined with studies of postmortem brain tissue from Parkinson's patients, to investigate the disease's early stages.

They discovered that toxic alpha-synuclein binds to a protein named Sec61A, blocking a crucial molecular gateway that assists newly synthesized proteins in entering the endoplasmic reticulum, a cell's protein-processing center. Blocking this gateway did not trigger the typical cellular stress response linked to endoplasmic reticulum damage but instead induced a different quality-control pathway called UFMylation.

This suggests that this previously unrecognized event marks the initial stage of Parkinson's disease. When the gateway is blocked, several vital proteins fail to reach the cell's recycling centers, known as lysosomes. Consequently, these lysosomes become less efficient at eliminating unwanted proteins and cellular waste. As a result, neurons release higher amounts of alpha-synuclein in small membrane-bound particles called extracellular vesicles, which can be detected in the bloodstream and may serve as early biomarkers for the disease.

The researchers found that several proteins affected by this blockage are encoded by genes often linked to an increased risk of Parkinson's disease. This implies that impairing this solitary protein-delivery pathway might explain how various genetic risk factors collectively contribute to the development of the disease. Furthermore, the team demonstrated that lowering toxic alpha-synuclein levels, either by reducing its production using CRISPR interference or by enhancing the activity of the proteasome, the cell's primary protein-clearance system, using drugs already approved for other medical conditions, can restore normal protein transport within cells.

Professor George Tofaris, the study's senior author, stated that this finding provides a unifying explanation for why diverse genetic risk factors for Parkinson's disease ultimately disrupt the same cellular processes. He also noted that reversing these defects in human neurons by boosting the cell's own protein-clearance machinery could potentially serve as an early treatment for Parkinson's disease, although further research is required before testing this approach in patients.