Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis. In this study, we exclusively disrupt the ATXN1-CIC interaction in vivo and show that it is at the crux of cerebellar toxicity in SCA1. Importantly, loss of CIC in the cerebellum does not cause ataxia or Purkinje cell degeneration. Expression profiling of these gain- and loss-of-function models, coupled with data from iPSC-derived neurons from SCA1 patients, supports a mechanism in which gain of function of the ATXN1-CIC complex is the major driver of toxicity. Rousseaux, Tschumperlin, Lu, and colleagues show that formation of the ATXN1-CIC complex is critical for polyQ-expanded ATXN1-mediated toxicity. They find that this complex mediates its effects through a gain-of-function mechanism in the cerebellum of SCA1 mice and SCA1 patient-derived neurons.
Bibliographical noteFunding Information:
This work was supported by grants NIH/NINDS R37 NS022920 , National Ataxia Foundation Pioneer Award , and Wallin Neuroscience Discovery Award to H.T.O.; NIH/NINDS R01 NS027699-17 and R37 NS027699 to H.Y.Z. and R01NS089664 and R01NS100874 to R.V.S.; CIHR Fellowship 201210MFE-290072-173743 and Parkinson’s Foundation grant PF-JfA-1762 to M.W.C.R.; and NIH/NINDS F32 NS083091 to Q.T. H.Y.Z. is an investigator of the Howard Hughes Medical Institute . The authors thank M.A. Durham and L.A. Lavery for discussions and reading the manuscript, the IPSC, neurobehavioral, and neuropathological cores of the Jan and Dan Duncan Neurological Research Institute, and the University of Minnesota Genomics Center and Stem Cell Institute. The project used cores supported in part by BCM IDDRC grant U54HD083092 from the Eunice Kennedy Shriver NICHD . Content is solely the responsibility of authors and does not necessarily represent the official views of the Eunice Kennedy Shriver NICHD and the NIH.
- RAN translation
- RNA toxicity