When the cellular “garbage trucks” of our brains break down, Parkinson’s disease may follow. New research from Yale University reveals how a key protein rushes to repair damaged cellular waste processors, potentially opening a window into why certain genetic mutations lead to this devastating neurological disorder.
The study, published April 10 in Nature Cell Biology, focuses on VPS13C, one of more than 20 genes whose mutations are known to cause familial forms of Parkinson’s disease. Researchers discovered this protein acts like a first responder, rapidly mobilizing to repair damaged lysosomes – the cell’s waste disposal units.
“Imagine a fire truck rushing to the scene to minimize damage—this mechanism is part of an emergency system that prevents leakage from a damaged lysosome,” explains Pietro De Camilli, professor of neuroscience and cell biology at Yale School of Medicine and the study’s senior author.
The research team found that VPS13C normally remains inactive in cells. However, within minutes of lysosome damage, the protein dramatically relocates to the damaged organelle. There, it forms a bridge between the lysosome and the endoplasmic reticulum—the cell’s lipid production center—allowing vital repair materials to flow to the damaged membrane.
When the researchers eliminated the VPS13C gene using CRISPR technology, cells couldn’t properly repair damaged lysosomes. This finding suggests that the protein’s absence may contribute to Parkinson’s disease by allowing toxic cellular waste to leak into brain cells.
Interestingly, another Parkinson’s-linked protein called LRRK2 also responds to lysosome damage, but much more slowly than VPS13C. “We have two proteins implicated in Parkinson’s disease and both come in to help repair lysosomes, but with different kinetics,” notes De Camilli.
The discovery adds to mounting evidence that lysosomal failure is a common thread in Parkinson’s disease. By understanding how multiple genetic factors converge on the same cellular process, researchers hope to develop treatments that could address various genetic causes simultaneously.
“If the functions of some of these genes converge on the same process, a therapeutic intervention that fixes the process could work as a magic bullet that prevents the defects generated by multiple genes,” De Camilli says.
For the millions living with Parkinson’s disease worldwide, these molecular insights represent a crucial step toward understanding the condition’s underlying causes – and potentially developing treatments that target its earliest stages, before symptoms even begin.
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