Scientists zero in on genetic causes of Parkinson’s – Innovita Research

Variants of at least 20 different genes have been closely linked to the development of Parkinson’s disease. However, scientists are still investigating how exactly they cause the severe and incurable motor disorder afflicts about 1 million people in the U.S. alone.

Image credit: Claudia Love on Unsplash, free license

New research by Yale researchers offers essential clues. In two new papers, scientists provide insight into the function of a protein called VPS13C, one of the molecular suspects underlying Parkinson’s, a disease marked by uncontrollable movements including tremors, stiffness, and loss of balance.

There are many roads to Rome; likewise, there are many roads leading to Parkinson’s,” said Pietro De Camilli, the John Klingenstein Professor of Neuroscience and professor of cell biology at Yale and investigator for the Howard Hughes Medical Institute. “Laboratories at Yale are progressing toward elucidating some of these paths.”

De Camilli is the senior author of the two new papers published in the Journal of Cell Biology and Proceedings of the National Academy of Science (PNAS).  

Previous studies have shown that mutations of the gene VPS13C cause rare cases of inherited Parkinson’s or an increased risk of the disease. To better understand why, De Camilli and Karin Reinisch, the David W. Wallace Professor of Cell Biology and of Molecular Biophysics and Biochemistry, have investigated the mechanisms by which these mutations lead to dysfunction on a cellular level.

In 2018 they reported that VPS13C forms a bridge between two subcellular organelles — the endoplasmic reticulum and the lysosome. The endoplasmic reticulum is the organelle that regulates the synthesis of most phospholipids, fatty molecules essential for building cell membranes. The lysosome acts as cell’s digestive system. They also showed that VPS13C can transport lipids, suggesting that it may form a conduit for the traffic of lipid between these two organelles.

One of the new papers from De Camilli’s lab demonstrates that the lack of VPS13C affects the lipid composition and properties of lysosomes. Moreover, they found that in a human cell line these perturbations activate an innate immunity. Such activation, if occurring in brain tissue, would trigger neuroinflammation, a process implicated in Parkinson’s by several recent studies.

The second paper from De Camilli’s lab uses state-of-the-art cryo-electron tomography techniques to reveal the architecture of this protein in its native environment supporting a bridge model of lipid transport. Jun Liu, a professor of microbial pathogenesis at Yale, is the co-corresponding author of this study.

Understanding these fine-grained molecular details will be crucial in understanding at least one of the roads leading to Parkinson’s disease and may help identify therapeutic targets to prevent or slow the disease, researchers say.

Source: Yale University