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Interactions Between SNX14 and its Homologue SNX13 in Cerebellar Ataxia

Annie Abioye 1,2, Vanessa B. Sanchez 1-3, Yijing Zhou 1,2, Naiara Akizu, PhD 1,2 1. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 2. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 3. Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Poster # 88

Disruption to lipid homeostasis underlies the pathogenesis of many genetic neurodegenerative disorders. However, the mechanisms involved in regulating neuronal lipid metabolism and their effect on disease remain largely unknown. Mutations in SNX14, a sorting nexin protein, is the cause of a cerebellar neurodegeneration syndrome known as SCAR20. SNX14 is a protein involved in the endoplasmic reticulum (ER)-lipid droplet (LD) tethering, thus regulating lipid storage and homeostasis. Our lab has recently generated a Snx14 knockout (KO) mouse model, which recapitulates the clinical features of SCAR 20, including motor deficits and cerebellar Purkinje cell degeneration. Lipidomic analysis revealed the lipid profile of the Snx14 KO mouse tissue showing an accumulation of Acylcarnitines (AcCA) associated with selective neurodegeneration. To better understand the neuronal specific function of SNX14 and uncover potential coregulators of neural lipid metabolism, our lab analyzed neuronal SNX14 interactome by liquid chromatography mass spectrometry (LC-MS) of immunoprecipitated Flag-tagged Snx14. This unveiled SNX13 as a major interacting protein of SNX14. Despite little knowledge about Snx13, our lab has shown that transcripts for both SNX13 and SNX14 are abundant in cerebellar Purkinje cells. Interestingly, we have also identified two siblings diagnosed with an ataxia syndrome and carrying homozygous truncating mutations in SNX13. This and ongoing research in our lab suggest that SNX13 and SNX14 have conserved roles in neuronal lipid homeostasis and their disruption leads to neurodegeneration.

LIGHTNING TALK - 2023 MidAtlantic Bioinformatics Conference

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