# Unraveling the mechanisms of motor neuron degeneration if Spinocerebellar Ataxia, type 1

> **NIH NIH K08** · BAYLOR COLLEGE OF MEDICINE · 2021 · $189,431

## Abstract

PROJECT SUMMARY/ABSTRACT
Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disease characterized by progressive
ataxia from cerebellar degeneration. Death typically occurs by the third to sixth decade of life. While the
hallmark of SCA1 is loss of motor coordination or ataxia, at the end stage of disease premature death results
from complications secondary to bulbar dysfunction, including swallowing difficulties and breathing dysfunction.
In SCA1, disease is caused by expansion of CAG repeats encoding poly-glutamine (polyQ) in ATAXIN1
(Atxn1). Substantial effort has been invested in determining the molecular mechanism leading to cerebellar
degeneration, specifically Purkinje cell death, from polyQ expanded Atxn1. This is largely due to the fact that
Purkinje cells seem to be the first neurons affected in SCA1 and they are most vulnerable to the pathogenic
sequelae of expanded polyQ Atxn1. However, loss of Purkinje cells does not account for the bulbar dysfunction
phenotype, which ultimately causes premature death. I hypothesize that motor neuron degeneration is
responsible for bulbar dysfunction in SCA1. Further supporting this hypothesis is SCA1 autopsy data showing
marked loss of motor neurons in the brainstem. In 2002 our lab developed a pivotal mouse model for SCA1
recapitulating the major human features of disease with robust face and construct validity. In this model,
designated Atxn1-154Q, 154 CAG repeats were knocked into the endogenous mouse Atxn1 gene locus. Upon
joining the Zoghbi lab, with my clinical expertise in neuromuscular diseases, I made the exciting observation
that these mice display overt signs of motor neuron degeneration. In particular I noted significant muscle
wasting, breathing abnormalities and spasticity by 24 weeks of age. The goals of this proposal are to examine
motor neurons in Atxn1-154Q mice functionally, morphologically and molecularly in order to better understand
what causes their degeneration and to establish these mice as an ideal model to study motor neuron
degeneration in SCA1.

## Key facts

- **NIH application ID:** 10232249
- **Project number:** 5K08NS102396-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** James P Orengo
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $189,431
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232249

## Citation

> US National Institutes of Health, RePORTER application 10232249, Unraveling the mechanisms of motor neuron degeneration if Spinocerebellar Ataxia, type 1 (5K08NS102396-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10232249. Licensed CC0.

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