# Nonneuronal Mechanisms of Polyglutamine Neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $477,978

## Abstract

Spinocerebellar Ataxia type 3 (SCA3), also known as Machado-Joseph disease, is one of at least nine
diseases caused by CAG repeat expansions that encode abnormally long polyglutamine tracts in the disease
proteins. Despite advances in disease understanding, much remains unknown about how the CAG expansion
in the SCA3 disease gene, ATXN3, causes brain dysfunction and cell death. We recently discovered selective
oligodendrocyte vulnerability across SCA3 mouse disease brain regions and identified early and robust
changes that implicate oligodendrocytes in disease pathogenesis. Our long-term objective is to understand
pathogenic mechanisms in SCA3 and related polyglutamine diseases so that therapies targeting the most
promising molecular and cellular targets can be developed for these fatal and currently untreatable disorders.
Toward that objective, the team of investigators will leverage their diverse research expertise and a wide range
of model systems including primary cell cultures, mouse models, and human disease tissue. Building on recent
discoveries in mouse models and human disease tissue, we will investigate nonneuronal contributions to
disease pathogenesis, with an emphasis on cells of the oligodendroglial lineage. In Aim 1, we will determine
how widespread oligodendrocyte dysfunction is in SCA3 disease. In Aim 2, we will generate novel conditional
SCA3 mouse models to establish if the mutant protein elicits cell-autonomous oligodendrocyte dysfunction and
define oligodendrocyte dysfunction contributions to disease pathogenesis. In Aim 3, we will elucidate the
molecular mechanisms that underlie oligodendrocyte dysfunction in SCA3 disease. Results of these studies
will help guide therapeutic development in SCA3 and related polyglutamine diseases.

## Key facts

- **NIH application ID:** 10272712
- **Project number:** 1R01NS122751-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Hayley S McLoughlin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $477,978
- **Award type:** 1
- **Project period:** 2021-09-30 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10272712

## Citation

> US National Institutes of Health, RePORTER application 10272712, Nonneuronal Mechanisms of Polyglutamine Neurodegeneration (1R01NS122751-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10272712. Licensed CC0.

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