Nigrostriatal Degeneration Underpins Sensorimotor Dysfunction in an Inducible Mouse Model of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by moderately expanded CGG trinucleotide repeats in the 5' untranslated region (UTR) of the <i>FMR1</i> gene. Characterized by motor deficits such as action tremor and cerebellar gait ataxia, FXTAS is further distinguished by ubiquitin-positive intranuclear inclusions in neurons and glia. However, its clinical spectrum often overlaps with other neurodegenerative conditions such as Parkinson's disease (PD). Sensorimotor gating deficits, commonly associated with disorders affecting the nigrostriatal pathway such as PD, have been reported in FXTAS, but the underlying connection between these two phenotypes remains undetermined. In this study, we used the P90CGG mouse model of FXTAS, which expresses 90 CGG repeats upon doxycycline induction, to investigate sensorimotor gating deficits and their relationship to nigrostriatal degeneration. After induction, the P90CGG model exhibited late-onset impairments in prepulse inhibition (PPI), a cross-species measure of sensorimotor gating. These deficits coincided with pronounced nigrostriatal degeneration but occurred without evidence of inclusion formation in the substantia nigra. Our findings highlight nigrostriatal degeneration, which has not previously been reported in animal models of FXTAS, and suggest a potential link to sensorimotor gating dysfunction within the context of the disorder.