Mouse Models of the Fragile X Tremor/Ataxia Syndrome (FXTAS) and the Fragile X Premutation

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-developing neurodegenerative disease that develops in some carriers of the fragile X premutation (PM) as the result of a 55–200 CGG trinucleotide repeat expansion in fragile X mental retardation 1 gene (FMR1). CGG-repeat knockin mouse models have been developed that model much, but not all, of the molecular, histological, and neurobehavioral pathology seen in FXTAS and in some affected PM carriers. This includes elevated Fmr1 mRNA, reduced levels of fragile X mental retardation protein (FMRP), intranuclear inclusions in neurons and astrocytes, mild motor dysfunction resembling ataxia, anxiety, and cognitive impairments. These mice have provided insight into when disease processes become evident during development, the molecular mechanisms of pathology, and the scope of neurobehavioral involvement. Moreover, these mice are being used pre-clinically to develop and test possible treatment approaches that may improve neurological function in affected individuals. This chapter describes the features of FXTAS, recently recognized pathology in some affected PM carriers, and the development and use of mouse models to study these disorders.