# Identifying symptomatic and neuroprotective strategies for cerebellar ataxia

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $483,151

## Abstract

A remarkable feature of the neurodegenerative spinocerebellar ataxias (SCAs) is that glutamine
encoding CAG (polyQ) expansions in a diverse set of genes all cause Purkinje cell (PC) and brainstem neuron
degeneration. This fact suggests that these genetically distinct polyQ SCAs share key upstream pathogenic
events. While PC dysfunction may principally drive motor dysfunction in polyQ SCAs, brainstem dysfunction
more closely correlates with premature death. This proposal explores unifying molecular events causing
neuronal dysfunction and degeneration in ataxia, with a focus on the polyQ SCAs.
In a series of recent publications supported by new data, we identified alterations in potassium (K+)
channels as a key feature in several polyQ SCAs. Importantly, in SCA1 transgenic mice, we previously showed
that restoring K+ channel expression or function rescued membrane hyperexcitability, improved motor
dysfunction and reduced PC degeneration. It is now important to examine the links between K+ channel
dysregulation and altered membrane excitability in cerebellar and brainstem neurons, and the relationship of
these events to motor dysfunction and neurodegeneration in several polyQ SCAs.
In the prior funding period we identified K+ channel dysfunction as the basis of PC spiking abnormalities
in models of the polyQ ataxias SCA1, SCA2, SCA3 and SCA7, which together account for the majority of
SCAs. To explore shared links between neuronal dysfunction and these functionally diverse polyQ disease
proteins, we applied unbiased transcriptomics in models of SCA1, SCA2 and SCA7, and identified a common
theme, beginning early in disease: significant reduction in cerebellar transcripts for key ion channels important
for K+ channel function. Preliminary data also suggest a reduction in K+ channel transcripts in SCA1 medullary
brainstem neurons. The proposal seeks to determine whether altered K+ channel function tied to the biology of
diverse polyQ proteins in regulating the transcription and/or stability of ion channel transcripts is a unifying
mechanism underlying neuronal dysfunction and degeneration in polyQ SCAs through the following aims: Aim
1: Determine whether there is shared potassium channel dysfunction in cerebellar Purkinje cells and brainstem
neurons in SCA1. Aim 2: Determine whether shared Purkinje cell dysfunction is responsible for motor
dysfunction and neurodegeneration in SCA1, SCA2 and SCA7. Aim 3: Define the basis for shared reduction in
ion channel transcripts in SCA1, SCA2 and SCA7. We anticipate that successful completion of these studies
will definitively establish the important role of K+ channel dysfunction in the disease pathogenesis of a wide
variety of polyQ ataxias. Further, these studies will demonstrate that abnormal Purkinje neuron spiking causes
motor dysfunction in SCAs Lastly, the proposed work will also answer whether K+ channels are compelling
therapeutic targets to counter cerebellar and brainstem dysfunction in cerebellar atax...

## Key facts

- **NIH application ID:** 9913591
- **Project number:** 5R01NS085054-07
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Vikram Govindaraju Shakkottai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $483,151
- **Award type:** 5
- **Project period:** 2013-09-30 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913591

## Citation

> US National Institutes of Health, RePORTER application 9913591, Identifying symptomatic and neuroprotective strategies for cerebellar ataxia (5R01NS085054-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9913591. Licensed CC0.

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