# CGG repeat associated translation in Fragile X-associated Tremor/Ataxia Syndrome

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $473,186

## Abstract

Fragile X-associated tremor/Ataxia syndrome (FXTAS) is one of a large class of human neurological disorders
that result from instability and expansion of nucleotide repeats. In FXTAS, a CGG nucleotide repeat expands in
the 5’ untranslated region of the fragile X gene, FMR1, and triggers formation of aggregated protein inclusions
in the patient brains. Our group found that the FXTAS CGG repeat gets translated into toxic homopolymeric
proteins despite its location outside of a canonical open reading frame through a process known as repeat
associated Non-AUG initiated (RAN) translation. RAN translated proteins accumulate in patient tissues and
contribute to CGG repeat associated toxicity in multiple model systems. In this proposal, we will explore how
this alternative translational initiation occurs mechanistically. Our preliminary data suggests that RAN
translation at CGG repeats is selectively enhanced by cellular stress, which typically blocks protein synthesis.
In parallel, CGG repeats directly elicit cellular stress and trigger stress granule formation. Our central
hypothesis is that CGG RAN translation and cellular stress participate in a feed-forward loop that drives
neurodegeneration. Our collaborative team will directly test this hypothesis by using biochemical techniques
as well as drosophila, mouse and human induced pluripotent stem cell models of FXTAS. In Aim 1 we will
determine how cellular stress selectively activates RAN translation, focusing specifically on initiation factors
that underlie this process. In Aim 2, we will elucidate how CGG repeats elicit cellular stress and influence
stress granule dynamics and whether interventions in this process impact repeat toxicity. In Aim 3, we will test
whether selective blockade of cellular stress pathways can disrupt this feed forward loop and alleviate CGG
repeat associated toxicity across disease models. Together, these studies will illuminate critical events in the
pathogenesis of FXTAS and other nucleotide repeat expansion disorders while rigorously testing two
complementary & innovative approaches to selective RAN translation blockade.

## Key facts

- **NIH application ID:** 10328912
- **Project number:** 5R01NS086810-08
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Peter K Todd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $473,186
- **Award type:** 5
- **Project period:** 2014-04-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328912

## Citation

> US National Institutes of Health, RePORTER application 10328912, CGG repeat associated translation in Fragile X-associated Tremor/Ataxia Syndrome (5R01NS086810-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10328912. Licensed CC0.

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