Parkinson’s disease may occur later when the cells of our brain “garbage trucks” break down. New Yale University research reveals how key proteins are rushing to repair damaged cell waste processors and potentially open a window into the causes of certain genetic mutations that lead to this devastating neurological disease.
The study, published April 10 in Natural Cell Biology, focuses on VPS13C, one of more than 20 genes whose mutations are known to cause familial Parkinson’s disease. The researchers found that the protein acts like a first responder, quickly mobilizing to repair damaged lysosomes-cell waste disposal units.
“Imagine a fire truck rushing to the scene to minimize damage, part of an emergency system of professors of neuroscience and cell biology at Yale School of Medicine to prevent damaged lysosomes from leaking.”
The team found that VPS13C usually remains inactive in cells. However, within minutes of lysosomal damage, the protein transfers sharply into damaged organelles. There, it forms a bridge between the lysosome and the endoplasmic reticulum (the lipid production center of the cell), allowing important repair materials to flow to the damaged membrane.
When researchers used CRISPR technology to eliminate the VPS13C gene, cells were unable to properly repair the damaged lysosomes. This finding suggests that protein deletion may lead to Parkinson’s disease by allowing toxic cellular waste to penetrate into brain cells.
Interestingly, another Parkinson’s protein called LRRK2 also responds to lysosome damage, but is much slower than VPS13C. “We have two proteins associated with Parkinson’s disease, both of which can help repair lysosomes, but with different kinetics,” de Camilli noted.
This finding adds to growing evidence that lysosomal failure is a common clue to Parkinson’s disease. By understanding how multiple genetic factors fuse in the same cellular process, researchers hope to develop treatments that can address a variety of genetic causes simultaneously.
“If the functions of some of these genes come together in the same process, the therapeutic interventions that repair the process can be used as magic bullets to prevent defects created by multiple genes,” De Camilli said.
For millions of lives with Parkinson’s disease worldwide, these molecular insights represent a critical step in understanding the root cause of the disease and have the potential to develop treatments targeting its earliest stages before symptoms begin.
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