title: Proteolytic cleavage of ataxin-7 promotes SCA7 retinal degeneration and neurological dysfunction.
abstract: The neurodegenerative disorder spinocerebellar ataxia type 7 (SCA7) is caused by a polyglutamine (polyQ) expansion in the ataxin-7 protein, categorizing SCA7 as one member of a large class of heritable neurodegenerative proteinopathies. Cleavage of ataxin-7 by the protease caspase-7 has been demonstrated in vitro, and the accumulation of proteolytic cleavage products in SCA7 patients and mouse models has been identified as an early pathological change. However, it remains unknown whether a causal relationship exists between ataxin-7 proteolysis and in vivo SCA7 disease progression. To determine whether caspase cleavage is a critical event in SCA7 disease pathogenesis, we generated transgenic mice expressing polyQ-expanded ataxin-7 with a second-site mutation (D266N) to prevent caspase-7 proteolysis. When we compared SCA7-D266N mice with SCA7 mice lacking the D266N mutation, we found that SCA7-D266N mice exhibited improved motor performance, reduced neurodegeneration and substantial lifespan extension. Our findings indicate that proteolysis at the D266 caspase-7 cleavage site is an important mediator of ataxin-7 neurotoxicity, suggesting that inhibition of caspase-7 cleavage of polyQ-ataxin-7 may be a promising therapeutic strategy for this untreatable disorder.
authors: Department of Medicine (Medical Genetics) and.
authors: Stephan J
authors: SJ
authors: Guyenet
authors: The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors: Shona S
authors: SS
authors: Mookerjee
authors: The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors: Amy
authors: A
authors: Lin
authors: Department of Medicine (Medical Genetics) and.
authors: Sara K
authors: SK
authors: Custer
authors: The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors: Sylvia F
authors: SF
authors: Chen
authors: Department of Neurology, University of Washington, Seattle, WA, USA.
authors: Bryce L
authors: BL
authors: Sopher
authors: Department of Medicine (Medical Genetics) and Department of Cellular and Molecular Medicine, Division of Biological Sciences, Institute for Genomic Medicine, and the Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA, Department of Neurosciences, Division of Biological Sciences, Institute for Genomic Medicine, and the Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA, Department of Pediatrics, Division of Biological Sciences, Institute for Genomic Medicine, and the Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA and Rady Children's Hospital, San Diego, CA 92123, USA alaspada@ucsd.edu lellerby@buckinstitute.org.
authors: Albert R
authors: AR
authors: La Spada
authors: The Buck Institute for Research on Aging, Novato, CA 94945, USA, alaspada@ucsd.edu lellerby@buckinstitute.org.
authors: Lisa M
authors: LM
authors: Ellerby
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D000067719:Ataxin-7 / Q000235:genetics / Q000378:metabolism*; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000628:therapy; D010455:Peptides / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D011689:Purkinje Cells / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics* / Q000628:therapy
chemical_list: D000067719:Ataxin-7; D010455:Peptides; C097188:polyglutamine; D001224:Aspartic Acid; C505520:CASP7 protein, human; C505524:Casp7 protein, mouse; D053179:Caspase 7