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Synergy between CGG Repeat RNA and RAN translation drives FXTAS pathogenesis through Protein Kinase R

ABSTRACT: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by transcribed CGG repeat expansions in the 5′ untranslated region of FMR1. Both CGG repeat RNA and repeat-associated non-AUG (RAN) translation of the polyglycine-containing protein FMRpolyG are implicated in FXTAS pathogenesis, but how these processes interact to drive neurodegeneration remains unclear. To define their relative contributions, we performed behavioral, histological, biochemical, and transcriptomic analyses in mice expressing AAV-delivered FMR1 repeats in sequence contexts that separated repeat RNA elicited toxicity from FMRpolyG-associated effects. RAN translation-competent CGG repeats induced FXTAS-like phenotypes, including FMRpolyG- and p62-positive intranuclear inclusions, gliosis, microglial activation, motor impairment, and Purkinje cell loss. In contrast, neither CGG repeat RNA engineered to reduce FMRpolyG production nor FMRpolyG expressed independently of repeat RNA recapitulated these neuroinflammatory, behavioral, or neurodegenerative phenotypes. Mechanistically, deletion or inhibition of protein kinase R (PKR) reduced CGG repeat-induced stress signaling and RAN translation in cellular models and attenuated behavioral, inflammatory, and inclusion pathology in FXTAS model mice. These findings support a model whereby PKR-dependent stress activation by CGG repeat RNA enhances RAN translation and downstream neurodegeneration and identifies PKR as a potential therapeutic target for FXTAS.

ORGANISM(S): Mus musculus

PROVIDER: GSE347172 | GEO | 2026/09/16

REPOSITORIES: GEO

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