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Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine (Q) encoding CAG repeats in the gene Ataxin-1 (ATXN1). Although motor and balance deficits are the core symptoms of SCA1, cognitive decline is also commonly observed in patients. While mutant ATXN1 is expressed throughout the brain, pathological findings reveal severe atrophy of cerebellar cortex in SCA1 patients. The cerebellum has recently been implicated in diverse cognitive functions, yet to what extent cerebellar neurodegeneration contributes to cognitive alterations in SCA1 remains poorly understood. Much of our understanding of the mechanisms underlying pathogenesis of motor symptoms in SCA1 comes from mouse models. Reasoning that mouse models could similarly offer important insights into the mechanisms of cognitive alterations in SCA1, we tested cognition in several mouse lines using Barnes maze and fear conditioning. We confirmed cognitive deficits in  Atxn1 154Q/2Q    knock-in mice with brain-wide expression of mutant ATXN1 and in ATXN1 null mice. We found that shorter polyQ length and haploinsufficiency of ATXN1 do not cause significant cognitive deficits. Finally,  ATXN1[82Q ]  transgenic mice—with cerebellum limited expression of mutant ATXN1—demonstrated milder impairment in most aspects of cognition compared to  Atxn1 154Q/2Q    mice, supporting the concept that cognitive deficits in SCA1 arise from a combination of cerebellar and extra-cerebellar dysfunctions.

Cerebellar contribution to the cognitive alterations in SCA1: evidence from mouse models