# Contribution of RAN proteins to HD, SCA3 other CAG.CTG expansion diseases

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2022 · $610,876

## Abstract

Project Summary
Since we discovered repeat associated non-ATG (RAN) RAN translation in 2011, we and
others have shown that RAN proteins accumulate in nine different expansion disorders. These
proteins, which can be expressed from both sense and antisense expansion transcripts,
accumulate in disease-relevant human tissues including spinocerebellar ataxia type 8 (SCA8)
and Huntington disease (HD). We now have evidence that polySer and polyLeu RAN proteins
accumulate in a group of spinocebellar ataxias (SCA1, 2, 3, 6 and 7) in which the CAG·CTG
expansion mutations are located in polyGln open reading frames. Additionally, we have
developed AAV and small molecule approaches to inhibit RAN translation. We will use these
tools and genetic approaches to test our central hypotheses that RAN protein pathology is a
common feature shared across polyglutamine encoding CAG·CTG expansion disorders and
that inhibiting the PKR pathway will reduce RAN protein levels and mitigate disease.
We will address our central hypothesis in three specific aims (1) To test the hypothesis that
RAN proteins contribute to spinocerebellar ataxias (SCAs) caused by polyglutamine encoding
CAG·CTG repeat expansion mutations. (2) To test the hypothesis that SCA and HD RAN
proteins are toxic and PKR inhibition will decrease RAN protein levels and improve cellular
phenotypes in HD and SCA3 iPSC derived cells (3) : To test the hypothesis that RAN proteins
contribute to HD and SCA3 phenotypes in mice independent of polyGln effects using genetic
and pharmacological approaches. Taken together these specific aims will determine the
contribution of RAN proteins to HD,SCA3 and CAG·CTG repeat expansion disorders and
characterize PKR inhibition as a potential therapeutic approach for this large class of
devastating repeat expansion diseases.

## Key facts

- **NIH application ID:** 10450786
- **Project number:** 5R01NS117910-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Monica Banez-Coronel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $610,876
- **Award type:** 5
- **Project period:** 2021-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450786

## Citation

> US National Institutes of Health, RePORTER application 10450786, Contribution of RAN proteins to HD, SCA3 other CAG.CTG expansion diseases (5R01NS117910-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450786. Licensed CC0.

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