# Structural and Molecular Mechanisms for Dysregulation of Protein Kinase C Gamma in Cerebellar Ataxia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $633,428

## Abstract

Summary/Abstract
 The overall vision of our proposed research is to understand the structural, molecular, and cellular
mechanisms by which germline mutations in protein kinase C gamma (PKCg) drive the neuro-
degenerative disease Spinocerebellar Ataxia 14 (SCA14). PKCg is a Ca2+/diacylglycerol-regulated kinase
expressed only in neurons, including Purkinje cells whose degeneration is a hallmark of the almost 50
subtypes of SCA. We have assembled a team with extensive and complementary expertise in structural
biology of kinases and in PKC mechanisms to understand how these mutations alter the structure and
function of PKCg to contribute to the disease phenotype. The hypothesis driving this proposal is that
mutations are concentrated at specific regions of PKCg that break autoinhibitory contacts to enhance its
activity by a novel mechanism that evades normal quality control degradation. This evasion of
degradation may be a unique feature of the Ataxia mutations as cancer-associated mutations that break
autoinhibitory contacts destabilize PKC and shunt it to degradation. Such evasion of normal quality
control allows aberrantly active PKCg to enhance its signaling output, which in Purkinje cells in the
cerebellum leads to degeneration. Furthermore, we hypothesize that enhanced signaling by PKCg may
underlie the pathology of SCA, in general, as a large fraction of SCAs are caused by mutations in proteins
that control Ca2+ homeostasis or signaling. We aim to combine computational, structural, biochemical,
live-cell imaging, and phosphoproteomics approaches to understand the molecular details of how
disease-associated mutations in PKCg impact function, with the long-term future goal of using this
knowledge to treat this devastating disease.

## Key facts

- **NIH application ID:** 10817871
- **Project number:** 5R01NS120725-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** ALEXANDRA C. NEWTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $633,428
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817871

## Citation

> US National Institutes of Health, RePORTER application 10817871, Structural and Molecular Mechanisms for Dysregulation of Protein Kinase C Gamma in Cerebellar Ataxia (5R01NS120725-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10817871. Licensed CC0.

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