Etiology of cognitive decline in Spinocerebellar ataxia type 1

ABSTRACT Spinocerebellar ataxia type 1 (SCA1) is a chronic neurodegenerative disease characterized by progressive dysfunction of the cerebellum, impaired movement and cognitive decline. No effective treatments exist for this devastating and fatal disease, and thus there is a pressing need to increase our understanding of SCA1 pathogenesis. SCA1 is caused by the abnormal expansion of polyglutamine (Q) region in the ataxin-1 (ATXN1) protein. While motor deficits are well studied, the etiology of neurocognitive deficits in SCA1 remains unknown. We have begun to investigate etiology of the neurocognitive deficits in SCA1 by asking two basic questions: where in the brain and how does expression of mutant ATXN1 lead to cognitive deficits? We have already obtained data that strongly suggest that expression of mutant ATXN1 only in the cerebellar Purkinje cells (PC) is sufficient to cause cognitive decline in PC-specific transgenic SCA1 mice. However, relative contributions of cerebellar and extra-cerebellar dysfunctions to SCA1 cognitive deficits remain unknown. Regarding the how, our preliminary data show alterations in prefrontal cortex neuronal activity in SCA1 mice, supporting the notion that aberrant function of prefrontal cortex contributes to cognitive decline. Moreover, we hypothesize that the extent to which the cerebellum contributes to cognitive deficits and prefrontal cortex dysfunction is larger early in disease compared to late stages when extra-cerebellar regions become affected and are likely to also contribute to cognitive decline. The current proposal tests this hypothesis using floxedATXN1146Q/2Q mice, a novel humanized SCA1 mouse model that we recently created.