# Brain region specific contribution of the ATXN1/CIC interaction to Spinocerebellar ataxia type 1

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2021 · $39,705

## Abstract

Project Summary
Spinocerebellar ataxia type 1 (SCA1) is a fatal adult-onset neurodegenerative disease, characterized by loss of
balance, slight cognitive impairment, breathing dysfunction, and early lethality. This is due to selective
neurodegeneration of cerebellar Purkinje cells (PCs) as well as hippocampal and brainstem neurons. The
disease is caused by the expansion of CAG repeats, encoding the polyglutamine (polyQ) tract in ATAXIN-1
(ATXN1), a protein that is broadly expressed in the brain. Our lab generated an Atxn1154Q/2Q knock-in SCA1
mouse model, that expresses one modified Atxn1 allele in which 154 CAG repeats replaced the wild-type 2
CAGs, and that recapitulates all known features of human SCA1. Using biochemical and genetic studies, we
discovered that the polyQ expansion stabilizes ATXN1 and mediates cerebellar degeneration through enhanced
function with the transcriptional repressor Capicua (CIC). This ATXN1/CIC interaction is thought to cause
disease through a gain-of-function mechanism, in which CIC targets are hyper-repressed. Disruption of the
ATXN1/CIC interaction exclusively in cerebellar PCs, by expressing a modified ATXN1 transgene in PCs,
rescues all cerebellar phenotypes. Additionally, when CIC levels are decreased by 50% globally, we see SCA1
rescue in the cerebellum, but not in the hippocampus or brainstem. This suggests that we need further
knockdown of the ATXN1/CIC interaction or that other factors are driving disease in these brain regions. I
hypothesize that fully disrupting the polyglutamine expanded ATXN1/CIC interaction will reveal the
contributions this complex has to driving SCA1 toxicity in the brainstem and hippocampus. To test this,
we have generated a novel mouse model, in which the Atxn1154Q allele has two amino acid substitutions in
ATXN1’s ATXN1/HBP1 (AXH) domain, that are key for its interaction with CIC. Using this model, the
Atxn1154Q[V591A;S602D]/2Q, we will completely lose binding of mutant ATXN1 to CIC. We will perform behavioral,
histopathological, and molecular assays on this model to determine if fully losing the ATXN1/CIC interaction
rescues hippocampal and brainstem SCA1 phenotypes. This will allow us to determine if targeting this complex
is sufficient for treating SCA1, or if other factors need to be considered.

## Key facts

- **NIH application ID:** 10248563
- **Project number:** 5F31NS115296-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Stephanie Lynn Coffin
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $39,705
- **Award type:** 5
- **Project period:** 2019-09-07 → 2022-06-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248563

## Citation

> US National Institutes of Health, RePORTER application 10248563, Brain region specific contribution of the ATXN1/CIC interaction to Spinocerebellar ataxia type 1 (5F31NS115296-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10248563. Licensed CC0.

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