Project 2- FXTAS: Mechanisms and Modifiers

- Project 2 Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects individuals with premutation-length repeat expansions (55–~200 CGG repeats) in the 5’ untranslated region of fragile X mental retardation 1 (FMR1). Common features of FXTAS include progressive intention tremor, gait ataxia, Parkinsonism, and cognitive decline. Penetrance is age-dependent but reduced in both male (~40%) and female (15%) carriers of the premutation (PM). The neuropathological hallmarks of FXTAS include ubiquitin- positive intranuclear inclusions throughout the brain and marked dropout of Purkinje neurons in the cerebellum. At the molecular level, FMR1 premutation alleles exhibit a 2 to 8-fold increase in FMR1 mRNA and expression of mutant mRNAs containing long (~100) CGG triplets has been shown to be toxic in cell and animal models. Two non-mutually exclusive molecular pathogenesis mechanisms for FXTAS: 1) RNA gain-of-function, in which the expression of expanded CGGs in RNA (rCGG) interferes with a subset of RNA-binding proteins (RBPs), functionally limiting their availability through sequestration, and 2) Repeat-associated non-AUG (RAN) translation, whereby translation through the rCGG (and/or antisense rCCG) repeats leads to the production of toxic homo-polypeptides, the most abundant of which is FMRpolyGlycine (FMRpolyG), that in turn interfere with cellular functions. Multiple mouse models have been developed and used by us and others to study these mechanisms. Previous work by Center investigators using model organisms (flies, mice) and cell models has identified several RBPs affected by expression of rCGGs. Altering expression of these proteins can modulate rCGG-mediated toxicity in model systems. RAN translation products are found in patient inclusions and mouse models and appear to also confer toxicity in numerous studies. Candidate genes showing potential as genetic modifiers have been identified using whole genome sequence (WGS) analysis of premutation carriers with early or late onset of FXTAS. Genetic screens in fly and mouse models have begun to demonstrate potential pathways for modifying penetrance or severity of PMs. In this project, we propose to confirm and extend identification of genetic modifiers through additional sequence analysis in a well-characterized cohort of FXTAS patients from, analyze modifiers of FXTAS in multiple mouse models of FXTAS, and investigate the role of the premutation in ribosome biogenesis, a cellular phenotype we have recently uncovered. In coordination with Projects 1 and 3, we expect to improve understanding of mechanisms that lead to FXTAS and other Fragile X-associated Disorders, especially Fragile X associated Primary Ovarian Insufficiency (FXPOI). Project Number: 1P50HD118707-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: David Nelson | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $478,510 | Activity Code: P50 | Study Section: Special Emphasis Panel[ZHD1 DSR-A (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1P50HD11870701