Spinocerebellar ataxia type 1 (SCA1) is a fatal adult-onset neurodegenerative disease, characterized by loss of balance, slight cognitive impairment, breathing dysfunction, and early lethality. This is due to selective neurodegeneration of cerebellar Purkinje cells (PCs) as well as hippocampal and brainstem neurons. The disease is caused by the expansion of CAG repeats, encoding the polyglutamine (polyQ) tract in ATAXIN-1 (ATXN1), a protein that is broadly expressed in the brain. Our lab generated an Atxn1154Q/2Q knock-in SCA1 mouse model, that expresses one modified Atxn1 allele in which 154 CAG repeats replaced the wild-type 2 CAGs, and that recapitulates all known features of human SCA1. Using biochemical and genetic studies, we discovered that the polyQ expansion stabilizes ATXN1 and mediates cerebellar degeneration through enhanced function with the transcriptional repressor Capicua (CIC). This ATXN1/CIC interaction is thought to cause disease through a gain-of-function mechanism, in which CIC targets are hyper-repressed. Disruption of the ATXN1/CIC interaction exclusively in cerebellar PCs, by expressing a modified ATXN1 transgene in PCs, rescues all cerebellar phenotypes. Additionally, when CIC levels are decreased by 50% globally, we see SCA1 rescue in the cerebellum, but not in the hippocampus or brainstem. This suggests that we need further knockdown of the ATXN1/CIC interaction or that other factors are driving disease in these brain regions. I hypothesize that fully disrupting the polyglutamine expanded ATXN1/CIC interaction will reveal the contributions this complex has to driving SCA1 toxicity in the brainstem and hippocampus. To test this, we have generated a novel mouse model, in which the Atxn1154Q allele has two amino acid substitutions in ATXN1?s ATXN1/HBP1 (AXH) domain, that are key for its interaction with CIC. Using this model, the Atxn1154Q[V591A;S602D]/2Q, we will completely lose binding of mutant ATXN1 to CIC. We will perform behavioral, histopathological, and molecular assays on this model to determine if fully losing the ATXN1/CIC interaction rescues hippocampal and brainstem SCA1 phenotypes. This will allow us to determine if targeting this complex is sufficient for treating SCA1, or if other factors need to be considered.
Spinocerebellar ataxia type 1 (SCA1) is a fatal adult onset neurodegenerative disease, characterized by degeneration of the cerebellum, hippocampus and brainstem. The disease driving protein in SCA1, ATAXIN-1 (ATXN1), has been shown to cause cerebellar toxicity by its interaction with transcriptional repressor Capicua (CIC). The goal of this project is to determine if the ATXN1-CIC complex is also driving disease pathology in the brainstem and hippocampus, which will inform us if targeting the ATXN1/CIC interaction is sufficient for treating SCA1 or if other factors need to be considered.
