Summary: New research clarifies how the VPS13C gene contributes to Parkinson’s disease.
Source: Yale
Researchers have linked variants in at least 20 genes to Parkinson’s disease, yet how many of these variants lead to the progressive motor symptoms—tremor, stiffness and impaired balance—remains unclear. New studies from Yale identify critical cellular roles for VPS13C, a gene associated with inherited and increased-risk forms of Parkinson’s, and outline mechanisms that could contribute to neurodegeneration.
Two companion papers from Yale scientists provide complementary insights into VPS13C function. One paper examines how loss of VPS13C alters lysosomal lipid composition and triggers innate immune signaling in human cells. The other uses advanced cryo-electron tomography to visualize the protein’s native architecture at membrane contact sites, supporting a bridge model for lipid transport between organelles.
“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 an investigator for the Howard Hughes Medical Institute. “Laboratories at Yale are making steady progress in mapping some of these pathways.” De Camilli is the senior author on both new papers, which were published in the Journal of Cell Biology and Proceedings of the National Academy of Sciences (PNAS).
Previous work demonstrated that VPS13C resides at contact sites between the endoplasmic reticulum (ER) and the lysosome. The ER synthesizes most cellular phospholipids—fatty molecules essential for membrane structure—while lysosomes perform degradation and recycling functions. Earlier studies also showed VPS13C can move lipids in vitro, suggesting the protein might form a conduit for lipid flow between these two organelles.
In the first of the new studies, De Camilli and colleagues show that absence of VPS13C alters the lipid landscape and biophysical properties of lysosomes. These lipid disturbances in a human cell line were sufficient to activate innate immune pathways. If similar events occur in brain tissue, the resulting neuroinflammation could contribute to neuronal dysfunction and degeneration—an idea consistent with growing evidence that inflammatory processes play a role in Parkinson’s disease.
The second paper employs state-of-the-art cryo-focused ion beam milling and cryo–electron tomography to visualize VPS13C in cells. Combining experimental imaging with structural predictions derived from AlphaFold, the team reconstructed a full-length model of human VPS13C. The model suggests an elongated rod roughly 30 nm long with a continuous hydrophobic groove capable of sheltering lipid molecules as they move between membranes.
By overexpressing full-length VPS13C or a truncated form together with its ER-binding partner VAP in cultured cells, the researchers identified rod-like densities that span the gap between ER and endo/lysosomal membranes. These in situ observations align with the predicted structures and provide direct visual support for the bridge-like mechanism of lipid transfer mediated by VPS13C.
Taken together, the two studies link VPS13C’s structural role in lipid transport to functional consequences at the lysosome and to downstream activation of innate immune pathways. Mapping these molecular details helps clarify one of the biological routes that can lead to Parkinson’s disease and highlights potential targets for therapies aimed at preventing or slowing disease progression.
About this genetics and Parkinson’s disease research news
Author: Bill Hathaway
Source: Yale
Contact: Bill Hathaway – Yale
Image: The image is in the public domain
Original Research: Closed access. “In situ architecture of the lipid transport protein VPS13C at ER–lysosome membrane contacts” by Shujun Cai et al., PNAS
Abstract
In situ architecture of the lipid transport protein VPS13C at ER–lysosome membrane contacts
VPS13 proteins are eukaryotic lipid transporters localized at membrane contact sites and have been proposed to transfer lipids between adjacent bilayers via a bridge-like mechanism. Until now, direct evidence from full-length structures and in situ electron microscopy has been limited. Leveraging AlphaFold predictions together with available structural data, researchers generated a full-length model of human VPS13C—a Parkinson’s disease–linked paralog localized at ER–endo/lysosome contacts. The predicted structure is an approximately 30-nanometer rod featuring a hydrophobic groove that extends the protein’s length.
To determine whether this architecture exists in cells, the team combined genetic manipulation with cryo-focused ion beam milling and cryo–electron tomography to analyze HeLa cells overexpressing full-length or internally truncated VPS13C alongside VAP, its ER anchoring partner. These experiments revealed rod-like densities spanning the intermembrane space that correspond to the predicted full-length and truncated VPS13C structures, providing in situ support for a bridge model of lipid transport by VPS13 family proteins.