Snx-rgs proteins in cerebellar function and disease Vanessa Breanne Sanchez

Format:

Book

Thesis/Dissertation

Author/Creator:

Sanchez, Vanessa Breanne, author.

Contributor:

University of Pennsylvania. Neuroscience., degree granting institution.

Language:

English

Subjects (All):

Neurosciences.

Cellular biology.

Molecular biology.

Pathology.

Genetics.

0317.

0379.

0307.

0369.

0571.

Local Subjects:

Neurosciences.

Cellular biology.

Molecular biology.

Pathology.

Genetics.

0317.

0379.

0307.

0369.

0571.

Genre:

Academic theses

Physical Description:

1 online resource (177 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

Genetic mutations that disrupt lipid metabolism are increasingly recognized as key contributors to the pathogenesis of many neurodegenerative diseases. Mutations in SNX14 cause spinocerebellar ataxia recessive 20 (SCAR20) characterized by progressive cerebellar degeneration and intellectual disability. SNX14, together with SNX13, SNX19, and SNX25 belong to the conserved SNX-RGS family of interorganelle tethering proteins. We first sought to determine if altered cellular lipid homeostasis is implicated in the pathogenesis of SCAR20. Here, we applied bulk RNA-sequencing, ultrastructure imaging, lipidomics, primary cerebellar cultures, histological and behavioral analysis of a SCAR20 mouse model. We find that our mouse model recapitulates human SNX14 deficiency at a genetic and phenotypic level. Notably, we demonstrate that cerebellar Purkinje cells are selectively vulnerable to the loss of Snx14 while the cortex remains intact. Our ultrastructure and lipidomic analysis of SNX14-deficient cerebellar reveal widespread lipid storage and metabolism defects. In addition, we observed telolysosome enlargement, defects in lipid droplet content, and swelling of the endoplasmic reticulum, suggesting that lipotoxicity is the pathogenic mechanism of SNX14 deficiency. Recent structural predictions suggest that SNX-RGS proteins contain a putative lipid transport protein (LTP) module containing a large hydrophobic cavity that is capable of binding to and transporting lipids. We show that this LTP module can bind to phospholipids with a preference for phosphatidic acid (PA), a non-bilayer lipid which perturbs membranes when accumulated. In line with this, we find that SNX-RGS protein depletion leads to pathological accumulation of PA and diacylglycerol on lysosomes, disrupting lysosome lipid composition. Following lysosome membrane permeabilization (LMP), we find SNX-RGS proteins, SNX13 and SNX14 are recruited to damaged lysosomes, and their loss perturbs lysosome membrane damage and repair. Using lysosome immunoprecipitation (LysoIP)-based proteomics in cultured cells, we show loss of SNX13 or SNX14 cause lysosome deacidification and blunts the recruitment of ESCRTs and other LMP repair machinery to damaged lysosomes. Finally, we identify a novel cerebellar ataxia resulting from loss of SNX13 and propose that SNX13 and SNX14 function as LTPs that support lysosome membrane integrity in neurons. In summary, my thesis work demonstrates that SNX13 and SNX14 are key players at the forefront of maintaining neuronal lipid and lysosomal homeostasis

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: Akizu, Naiara Committee members: Orthmann-Murphy, Jennifer L.; Ortiz-Gonzalez, Xilma; Davidson, Beverly L.; Henne, W. Mike

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247972747

Access Restriction:

Restricted for use by site license