Harry T. Orr, PhD, Institute for Translational Neuroscience, Dept of Laboratory Medicine and Pathology, University of Minnesota

Spinocerebellar ataxia type 1 (SCA1) is one of nine dominantly inherited neurodegenerative diseases caused by expansion of a translated CAG repeat encoding a glutamine tract. In SCA1, this polyQ tract lies within the Ataxin-1 (ATXN1) protein. Prominent sites of SCA1 pathology are Purkinje cells of the cerebellar cortex. Genetic and molecular studies using mouse models of SCA1 highlight key drivers for polyQ expansion-driven ATXN1 toxicity in the cerebellum. In addition, this work provides important insights into neurodegenerative disease more broadly. Among these are the importance of the normal function and biochemistry of ATXN1 in pathogenesis, an age-dependence to recovery from motor deficits characteristic of SCA1, and an intriguing relationship between cerebellar development with onset of neurodegeneration. Lastly, recent work reveals disease-associated transcriptome profiles that vary between regions of the CNS affected in SCA1.