# RNA Granules in Cerebellar Neurodegeneration

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $454,923

## Abstract

Neurodegenerative diseases represent an ever-increasing societal and economic burden with WHO estimates
indicating that they will replace cancer as the 2nd leading cause of death by 2040. In neurodegenerative
disease research, a wealth of pathways has been uncovered, but their direct and primary relevance to the
respective human disease has been difficult to prove and targeting of pathways has remained difficult. The
proposed work will characterize stress granules (SGs) in spinocerebellar ataxia type 2 (SCA2), a hereditary
neurodegenerative disease affecting cerebellar Purkinje neurons (PNs) and other neurons in the cerebellum,
brainstem and cerebrum. The cause of SCA2 is a gain-of-function CAG expansion in the ATXN2 gene
resulting in an expanded polyglutamine (polyQ) in ataxin-2. ATXN2 was previously known to have functions in
mRNA metabolism based on its interactions with multiple RNA binding proteins (RBPs) including
A2BP1/RBFOX1, DDX6, PABP1, TDP-43, FUS. We have now demonstrated that mutant ATXN2 interacts with
the SG protein Staufen1, and this interaction has specific effects on SGs. Staufen expression (but not DDX6 or
PABPC1) is increased with ATXN2 mutation, and we have also identified specific downstream consequences
of this interaction on the abundance of SG mRNAs directly interacting Staufen. The objective of the proposed
research is to characterize mechanistically why Staufen expression increases with ATXN2 mutation, to
characterize the proteomic and mRNA composition of SCA2 SGs in SCA2 patient fibroblasts and neurons and
in SCA2 transgenic mice. SG elements that are identified by this work might be exploited therapeutically for
treating SCA2. Three specific aims are proposed: 1) We will evaluate mutant ATXN2 inhibition of protein
autophagy as a reason for staufen overexpression, and will characterize SCA2 SG rate of formation, half-life,
and superstructure using superresolution microscopy, as well as SCA2 SG transcriptomes using purified SGs.
2) We will conduct FISH to localize SCA2 SG mRNAs in cultured SCA2 neurons and in cerebellar slices of
SCA2 mice. 3) We will determine SCA2 mouse motor and neurophysiological phenotypes in SCA2 mice
haploinsufficient for Staufen, and will record Purkinje cell firing frequencies simultaneously with imaging for
TIA1 positive SGs and calcium abundance. This will determine whether abnormal SG trafficking/localization
associates with abnormal PC physiology in SCA2 mice, depending on Staufen expression. The proposed work
will clarify the role for SGs in neurodegeneration and will aid in the identification of new avenues towards
treatments of SCA2 and other degenerative ataxias

## Key facts

- **NIH application ID:** 9910465
- **Project number:** 5R01NS097903-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Daniel R Scoles
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $454,923
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9910465

## Citation

> US National Institutes of Health, RePORTER application 9910465, RNA Granules in Cerebellar Neurodegeneration (5R01NS097903-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9910465. Licensed CC0.

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