# Molecular Basis of rCGG-Mediated Neurodegeneration

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $393,435

## Abstract

Project Summary:
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder
that affects the carriers of premutation alleles (55–200 CGG repeats) of the fragile X mental
retardation 1 (FMR1) gene. Common features of FXTAS include progressive intention tremor, gait
ataxia, Parkinsonism, and cognitive decline. The neuropathological hallmarks of FXTAS include
ubiquitin-positive intranuclear inclusions throughout brain and marked dropout of Purkinje neurons in
cerebellum. The long-term goal of this project is to understand the molecular pathogenesis of FXTAS
and develop effective therapeutic interventions for FXTAS. At the molecular level, FMR1 CGG
premutation carriers exhibit a 2 to 8-fold increase in FMR1 mRNA compared to control individuals.
Expression of mutant mRNAs containing long (~100) CGG triplets has been shown to be toxic in cell
and animal models. Currently, data support two non-mutually exclusive molecular pathogenesis
mechanisms for FXTAS: 1) RNA gain-of-function, in which rCGG repeat-binding proteins (RBPs)
become functionally limited through sequestration by lengthy rCGG repeats, and 2) Repeat-
associated non-AUG (RAN) translation, whereby translation through the CGG (or antisense CCG)
repeats leads to the production of toxic homo-polypeptides, such as FMRpolyG, which in turn interfere
with a variety of cellular functions. Our previous work has identified two known RNA-binding proteins,
Pur  and hnRNP A2/B1, as RBPs affected by expression of rCGG. We showed that increased
expression of either protein could modulate rCGG-mediated toxicity, supporting the RNA-mediated
sequestration model of FXTAS. To determine the contributions of both mechanisms to FXTAS
pathogenesis, we have generated transgenic lines of mice that express hnRNP A2/B1 and suppress
rCGG repeat-mediated toxicity. In parallel, we have taken both whole genome sequencing and global
metabolic profiling approaches combined with fly genetic screens to identify potential additional
genetic modifiers of FXTAS. We have found that PSMB5 and the sphingolipid metabolic pathway
could modulate rCGG repeat toxicity. In this proposal, we plan to further test the hypothesis that
FXTAS results from abnormal RNA metabolism stemming from inappropriate association of RBPs
with the RNA produced by FMR1 premutation alleles, as well as determine whether these additional
candidate modifiers can modulate FXTAS pathogenesis. Successful completion of these studies
should significantly advance our understanding the molecular pathogenesis of FXTAS. Identifications
of genes and pathways involved in FXTAS will provide valuable targets for future pharmacological
research aimed at developing drugs for therapy.

## Key facts

- **NIH application ID:** 10338196
- **Project number:** 5R01NS051630-17
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** David Loren Nelson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $393,435
- **Award type:** 5
- **Project period:** 2006-01-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10338196

## Citation

> US National Institutes of Health, RePORTER application 10338196, Molecular Basis of rCGG-Mediated Neurodegeneration (5R01NS051630-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10338196. Licensed CC0.

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