dataxin-2 mediates expanded ataxin-1-induced neurodegeneration in a drosophila model of sca1dataxin-2介导扩张ataxin-1-induced sca1果蝇模型神经退化.pdfVIP

dAtaxin-2 Mediates Expanded Ataxin-1-Induced Neurodegeneration in a Drosophila Model of SCA1 1,2 ´ 1 1 1 1 1 1 Ismael Al-Ramahi , Alma M. Perez , Janghoo Lim , Minghang Zhang , Rie Sorensen , Maria de Haro , Joana Branco , Stefan M. Pulst3, Huda Y. Zoghbi1,4,5, Juan Botas1* ´ 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America, 2 Departamento de Biologıa, Facultad de Ciencias- University Autonoma de Madrid, Madrid, Spain, 3 Division of Neurology, Cedars-Sinai Medical Center; Departments of Medicine and Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States of America, 4 Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America, 5 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, United States of America. Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative disorders sharing atrophy of the cerebellum as a common feature. SCA1 and SCA2 are two ataxias caused by expansion of polyglutamine tracts in Ataxin-1 (ATXN1) and Ataxin-2 (ATXN2), respectively, two proteins that are otherwise unrelated. Here, we use a Drosophila model of SCA1 to unveil molecular mechanisms linking Ataxin-1 with Ataxin-2 during SCA1 pathogenesis. We show that wild-type Drosophila Ataxin-2 (dAtx2) is a major genetic modifier of human expanded Ataxin-1 (Ataxin- 1[82Q]) toxicity. Increased dAtx2 levels enhance, and more importantly, decreased dAtx2 levels suppress Ataxin- 1[82Q]-induced neurodegeneration, thereby ruling out a pathog