Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a CAG repeat that encodes a polyglutamine tract in ATAXIN1 (ATXN1). Molecular and genetic data indicate that SCA1 is mainly caused by a gain-of-function mechanism. However, deletion of wild-type ATXN1 enhances SCA1 pathogenesis, whereas increased levels of an evolutionarily conserved paralog of ATXN1, Ataxin 1-Like, ameliorate it. These data suggest that a partial loss of ATXN1 function contributes to SCA1. To address this possibility, we set out to determine if the SCA1 disease model (Atxn1154Q/+ mice) and the loss of Atxn1 function model (Atxn1−/− mice) share molecular changes that could potentially contribute to SCA1 pathogenesis. To identify transcriptional changes that might result from loss of function of ATXN1 in SCA1, we performed gene expression microarray studies on cerebellar RNA from Atxn1−/− and Atxn1154Q/+ cerebella and uncovered shared gene expression changes. We further show that mild overexpression of Ataxin-1-Like rescues several of the molecular and behavioral defects in Atxn1 −/− mice. These results support a model in which Ataxin 1-Like overexpression represses SCA1 pathogenesis by compensating for a partial loss of function of Atxn1. Altogether, these data provide evidence that partial loss of Atxn1 function contributes to SCA1 pathogenesis and raise the possibility that loss-of-function mechanisms contribute to other dominantly inherited neurodegenerative diseases.
Author Summary Spinocerebellar Ataxia type 1 (SCA1) is one of nine neurodegenerative diseases caused by an increase in the number of the amino acid glutamine in their respective proteins. Genetic studies have pointed to the fact that the glutamine expansion in Ataxin-1 causes SCA1 by causing Ataxin-1 to gain some function(s). Here, we demonstrate that in addition to the toxic gain-of-function mechanism, partial loss of the normal functions of Ataxin-1 contributes to SCA1. Ataxin-1 forms protein complexes with Capicua, a protein that silences expression of other genes, and we found that in SCA1 mouse models the levels of these complexes are reduced, resulting in increased expression of some genes. We also demonstrate that increased levels of Ataxin-1-Like, a protein that is similar to Ataxin-1 and protects against mutant Ataxin-1 in mice, rescues molecular and behavioral defects in mice deficient in Ataxin-1. These results show that Ataxin-1-Like compensates for loss of Ataxin-1 and that Ataxin-1 and Ataxin-1-Like share some normal functions. Together, these findings suggest that rescue of SCA1 symptoms by Ataxin-1-Like could be partly due to restoration of lost normal functions of Ataxin-1 in mice that express the mutant polyglutamine-expanded Ataxin-1.