Scientists focus on genetic causes of Parkinson’s


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Summary: Study unveils role played by VPS13C gene in Parkinson’s disease.

Source: jale

Variants in at least 20 different genes have been closely linked to causing Parkinson’s disease, but scientists are still studying exactly how they cause the severe and incurable movement disorder that affects about 1 million people in the US alone.

New research from Yale researchers offers important clues. In two new publications, scientists provide insight into the function of a protein called VPS13C, one of the molecular suspects in Parkinson’s disease, a disease characterized by uncontrollable movements such as tremors, stiffness and loss of balance.

‚ÄúThere are many roads to Rome; Likewise, many roads lead to Parkinson’s,” said Pietro De Camilli, John Klingenstein professor of neuroscience and professor of cell biology at Yale and a researcher at the Howard Hughes Medical Institute. “Yale labs are making progress in elucidating some of these pathways.”

De Camilli is lead author of the two new articles that will be published in the Journal of Cell Biology and Proceedings of the National Academy of Science (PNAS).

Previous studies have shown that mutations in the VPS13C gene cause rare cases of hereditary Parkinson’s disease 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 Molecular Biophysics and Biochemistry, investigated the mechanisms by which these mutations lead to dysfunction at the 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, fat molecules essential for building cell membranes.

The lysosome functions as a cell’s digestive system. They also showed that VPS13C can transport lipids, suggesting that it could form a conduit for transporting lipids between these two organelles.

One of the new works from De Camilli’s lab shows that the absence of VPS13C affects the lipid composition and properties of lysosomes.

This shows DNA
Previous studies have shown that mutations in the VPS13C gene cause rare cases of hereditary Parkinson’s disease or an increased risk of the disease. The image is in the public domain

In addition, they found that these disorders activate innate immunity in a human cell line. Such activation, if it occurs in brain tissue, would trigger neuroinflammation, a process that has been linked to Parkinson’s disease in several recent studies.

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

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

About this news from genetics and Parkinson’s research

Author: Bill Hathaway
Source: jale
Contact: Bill Hathaway-Yale
Picture: The image is in the public domain

See also

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Original research: Closed access.
“In situ architecture of the lipid transport protein VPS13C at ER-lysosome membrane contacts” by Shujun Cai et al. PNAS


In situ architecture of the lipid transport protein VPS13C at ER lysosome membrane contacts

VPS13 is a eukaryotic lipid transport protein localized to membrane junctions. Previous studies suggested that it might transfer lipids between adjacent bilayers through a bridge-like mechanism. However, direct evidence for this hypothesis from a full-length structure and from in situ electron microscopic (EM) studies is still lacking.

Here, we used AlphaFold predictions to complement the already available structural information about VPS13 to create a complete model of human VPS13C, the Parkinson’s disease-associated VPS13 paralogue that occurs at junctions between the endoplasmic reticulum (ER) and Endo/lysosome localized . One such model predicts a 30 nm rod with a hydrophobic groove running its entire length.

We further investigated whether such a structure can be observed in situ at ER endo/lysosome contacts. To this end, we combined genetic approaches with cryofocused ion beam milling (cryo-FIB) and cryo-electron tomography (cryo-ET) to study HeLa cells expressing this protein (either full-length or with an internal truncation) along with VAP overexpress , its anchoring binding partner on the ER.

Using these methods, we identified rod-like densities spanning the space separating the two adjacent membranes that are consistent with the predicted structures of full-length VPS13C or its shorter truncated mutant, providing in situ evidence for a bridging model of VPS13 in lipid become transportation.

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