Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine tract in ataxin-1 (ATXN1). SCA1 pathogenesis studies support a model in which the expanded glutamine tract causes toxicity by modulating the normal activities of ATXN1. To explore native interactions that modify the toxicity of ATXN1, we generated a targeted duplication of the mouse ataxin-1-like (Atxn1l, also known as Boat) locus, a highly conserved paralog of SCA1, and tested the role of this protein in SCA1 pathology. Using a knock-in mouse model of SCA1 that recapitulates the selective neurodegeneration seen in affected individuals, we found that elevated Atxn1l levels suppress neuropathology by displacing mutant Atxn1 from its native complex with Capicua (CIC). Our results provide genetic evidence that the selective neuropathology of SCA1 arises from modulation of a core functional activity of ATXN1, and they underscore the importance of studying the paralogs of genes mutated in neurodegenerative diseases to gain insight into mechanisms of pathogenesis.
Bibliographical noteFunding Information:
by the following US National Institutes of Health grants: National Institute for Neurological Disorders and Stroke grants NS27699 (to H.Y.Z.), NS22920 and NS45667 (to H.T.O.) and National Institute of Child Health and Human Development grant HD024064 (to the Baylor College of Medicine Mental Retardation and Developmental Disabilities Research Center). A.B.B. was a postdoctoral fellow of the Hereditary Disease Foundation. H.Y.Z. is a Howard Hughes Medical Institute investigator.
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