Unraveling how VPS13C deficiency affects interorganellar lipid transport and lysosomal homeostasis and how this contributes to the neuropathogenesis of Dementia with Lewy Bodies

Dementia is the progressive loss of cognitive function that affects >50 million people worldwide. Dementia with Lewy bodies (DLB) is, after Alzheimer’s disease (AD), the second most prevalent cause of neurodegenerative dementia. Thus far, no causal genes have been identified making the exploration of underlying disease causing mechanisms very difficult, if not impossible. Whole genome sequencing recently identified compound heterozygous mutations in the VPS13C gene segregating with the disease in a family with DLB. Interestingly, VPS13C was first identified as a novel risk gene for Parkinson disease (PD) underscoring the broader involvement in this spectrum of dementias. Only mutations in both alleles result in DLB, indicating  loss of VPS13C function in the neuropathogenesis of DLB.
VPS13C localizes to contact sites between the endoplasmic reticulum, lysosomes and lipid droplets, implicating a function in membrane lipid homeostasis. However, how mutations in VPS13C lead to neurodegeneration is unknown. This project will bridge this knowledge gap by developing new tools, including antibodies, cellular and in vivo models. Using advanced imaging and molecular and cell biological strategies in different neuronal models, we aim to identify and validate new hVPS13C interactors and functions that will help us to understand the role of VPS13C on DLB neuropathogenesis. This knowledge may become instrumental for the identification of new biomarkers and the development of new therapie