# Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $25,125

## Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, progressive neurodegenerative disease that
causes severe motor deficits and cerebellar neuron degeneration. It is caused by a CAG-repeat expansion in
the gene Ataxin-1 (ATXN1). Although ATXN1 is fairly ubiquitously expressed throughout the brain, specific brain
regions and cell types have been shown to be selectively vulnerable to degeneration, including cerebellar
Purkinje cell neurons. In order to better understand the pathophysiology of this disease, several mouse models
have been developed and extensively utilized. However, most of these mouse models have been characterized
on a particular genetic background. For example, the Purkinje cell-specific transgenic SCA1 models have been
developed and maintained on a pure FVB/NJ background, including the B05 model, which express the human
disease-causing ATXN1 allele and recapitulate the behavioral deficits and pathological phenotypes observed in
human SCA1 patients. Interestingly, when we backcrossed and maintained this original B05 mouse line onto a
pure C57BL/6J genetic background, the SCA1-related behavioral motor deficit was no longer observed, however
the Purkinje cell degeneration phenotypes remained. These preliminary findings suggest that mouse genetic
background plays a crucial role in effectively modeling neurodegenerative diseases, such as SCA1, and
therefore, the interaction of mouse genetic background and disease symptoms should be further analyzed and
carefully controlled for in future experiments. In this supplement grant proposal, we will determine the precise
impact of different mouse genetic backgrounds towards SCA1 disease phenotypes, and elucidate the molecular
mechanisms through which mutant ATXN1 regulates motor behavior deficits and Purkinje cell degeneration. In
Aim 1, we will fully characterize the SCA1 mouse phenotypic differences between the two genetic backgrounds.
In Aim 2, we will determine the molecular pathways differentially affected in the SCA1 mouse cerebellum
between two different genetic backgrounds. We anticipate that this research will provide fundamental insights
into the impact of mouse genetic backgrounds towards neurodegenerative disease pathogenesis, and uncover
novel mechanisms through which SCA1 pathology is regulated. If successful, these studies will underscore the
importance of examining multiple genetic backgrounds in neurodegenerative diseases and reveal novel potential
entry points for therapeutic intervention in disorders in which ATXN1 mutations are associated, including SCA1,
frontotemporal dementia, and Alzheimer’s disease.

## Key facts

- **NIH application ID:** 10632309
- **Project number:** 3R01AG076154-01S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Janghoo Lim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $25,125
- **Award type:** 3
- **Project period:** 2022-03-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10632309

## Citation

> US National Institutes of Health, RePORTER application 10632309, Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases (3R01AG076154-01S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10632309. Licensed CC0.

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