# Investigating SNX13 in Cerebellar Function and Disease

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $36,651

## Abstract

PROJECT SUMMARY
Lipids are an essential component of neuronal function and structure. Genetic mutations associated with
disturbed lipid metabolism in neurodegenerative disorders is becoming increasingly recognized, yet the
mechanisms that regulate neuronal lipid metabolism is poorly understood. We and others have found SNX14, a
sorting-nexin (SNX) protein associated with a spinocerebellar ataxia (SCAR20), to be a regulator of endoplasmic
reticulum (ER)-lipid droplet (LD) biogenesis, fatty acid desaturation, and cerebellar lipid homeostasis. I have
discovered that SNX14 interacts with its paralog, SNX13, in neural cells. SNX13 is also an ER resident protein
that controls triglyceride content, LD numbers, and lysosomal cholesterol homeostasis. We recently identified
homozygous SNX13 variants in three children with a novel cerebellar ataxia similar to SCAR20. However, little
is known regarding the basic molecular mechanisms behind SNX13 function in neurons, and how depletion of
Snx13 leads to degeneration. My overarching hypothesis is that SNX13 functions in neuronal lipid homeostasis,
which is critical for cerebellar function and survival. To test this hypothesis, Aim 1 will knock down Snx13 by
AAV-mediated in vivo delivery of Snx13 sgRNAs to dCAS9-KRAB expressing mice to investigate the role of
Snx13 in cerebellar integrity and motor behavior. Aim 2 will leverage genome edited human pluripotent stem cell
derived neuronal cultures to define the impact of SNX13 patient mutations on LD homeostasis under conditions
of cellular stress (e.g., excess fatty acids and excitotoxicity). Successful completion of these aims will be an
important foundation for future studies investigating neuronal LD homeostasis, while simultaneously providing
me with outstanding training in CRISPR/Cas9 methodologies, stem cell biology, and behavior. Further, these
efforts will uncover basic disease mechanisms that can be used to inform targeted therapeutic strategies for
patients with SNX13 or SNX14 mutations, including other relevant neurodegenerative and metabolic disorders.
The proposed training plan is sponsored by Dr. Naiara Akizu and Dr. Beverly Davidson at the University of
Pennsylvania and Children’s Hospital of Philadelphia. This proposal provides a phenomenal training experience
that will expand my technical expertise in cellular neurobiology, and cultivate my professional skills in science
communication, mentoring, and leadership, all of which will facilitate my career goals of becoming a leading
researcher in the field of neurodegeneration.

## Key facts

- **NIH application ID:** 10935965
- **Project number:** 5F31NS130941-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Vanessa Breanne Sanchez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,651
- **Award type:** 5
- **Project period:** 2023-09-18 → 2025-09-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935965

## Citation

> US National Institutes of Health, RePORTER application 10935965, Investigating SNX13 in Cerebellar Function and Disease (5F31NS130941-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10935965. Licensed CC0.

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