# Metabolic Dysregulation in FXTAS Pathogenesis

> **NIH NIH R21** · EMORY UNIVERSITY · 2021 · $197,700

## Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects
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
the brain and marked dropout of Purkinje neurons in the cerebellum. 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. Multiple mouse models have been developed to study these mechanisms. Much
remains unknown regarding the metabolic alterations associated with FXTAS, especially in the brain, and the
most affected region, the cerebellum. Our previous work identified the metabolic alterations associated with
FXTAS pathogenesis using our FXTAS mouse model that expresses 90 CGG repeats in cerebellar Purkinje
neurons and exhibits the key phenotypic features of FXTAS. By combining global metabolic profiling with a
Drosophila genetic screen, we have found that the sphingolipid metabolic pathway can modulate rCGG repeat
toxicity. A preliminary study of 5 FXTAS postmortem brains compared to age-matched controls also identified
alterations in the sphingolipid pathway. Untargeted metabolomic analysis of plasma samples from men with
symptoms of FXTAS identified significant alterations in the sphingolipid pathway compared to noncarrier men.
In the proposed study, we will expand on these findings using additional FXTAS mouse models, Drosophila
models, and human samples. First, we will compare the lipidomic profile of a mouse model that expresses 99
CGG repeats and the FMRpolyG protein to a mouse model that expresses the expanded repeat without
expressing the FMRpolyG protein. In addition, we will test for amelioration of FXTAS pathogenesis in flies with
a drug that targets β-glucocerebrosidase (GBA), a key enzyme in the sphingolipid pathway that we have found
is able to modulate rCGG repeat toxicity. We will also investigate the profile in FXTAS patients using additional
post mortem brain samples and plasma samples that have been collected on a longitudinally-studied cohort for
FXTAS pathogenesis. Our proposed work investigating the metabolic changes in FXTAS will aid in the
identification of biomarkers as well as in understanding the pathogenesis of disease

## Key facts

- **NIH application ID:** 10224940
- **Project number:** 5R21AG065815-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Emily Graves Allen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $197,700
- **Award type:** 5
- **Project period:** 2020-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224940

## Citation

> US National Institutes of Health, RePORTER application 10224940, Metabolic Dysregulation in FXTAS Pathogenesis (5R21AG065815-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10224940. Licensed CC0.

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