Neuronal VPS13A depletion links diacylglycerol PKC signaling and synaptic spines.

Abstract

Background: Intermembrane lipid transfer protein VPS13A (VPS13A) is a large protein whose cellular functions are still under investigation. VPS13A gene mutations leading to the absence of protein expression cause Chorea-acanthocytosis (ChAc), an ultra-rare inherited neurodegenerative movement disorder. Although the molecular mechanisms linking VPS13A loss to neuronal dysfunction remain unclear, its role as a bulk lipid transfer protein suggests that impaired lipid distribution may represent a primary pathogenic mechanism leading to neurodegeneration in ChAc. In this study, we investigated the effect of neuronal silencing of VPS13A in a murine model to phenocopy the human disease.

Results: Lipidomics analysis revealed an increase in the concentration of several diacylglycerol species induced by VPS13A knockdown. We then explored the downstream molecular pathways related to the altered diacylglycerol levels and found that VPS13A knockdown induces a decrease in protein kinase C (PKC)βII concentration but an increase in PKCα/βII phosphorylation in cultured neurons. Finally, pharmacological inhibition of PKCβII reverted aberrant neuronal morphology and loss of spine density induced by VPS13A KD. These results underscore the importance of VPS13A in regulating neuronal lipid distribution, showing that its absence perturbs the diacylglycerol/PKC signaling pathway, with measurable effects on neuronal structure and synaptic density.

Conclusions: Overall, our results underscore a previously underappreciated role for VPS13A in the structural organization of neurons through lipid-mediated signaling mechanisms, providing insight into the cellular dysfunction underlying ChAc.