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Publication : Proteolytic cleavage of ataxin-7 promotes SCA7 retinal degeneration and neurological dysfunction.

First Author  Guyenet SJ Year  2015
Journal  Hum Mol Genet Volume  24
Issue  14 Pages  3908-17
PubMed ID  25859008 Mgi Jnum  J:222402
Mgi Id  MGI:5644576 Doi  10.1093/hmg/ddv121
Citation  Guyenet SJ, et al. (2015) Proteolytic cleavage of ataxin-7 promotes SCA7 retinal degeneration and neurological dysfunction. Hum Mol Genet 24(14):3908-17
abstractText  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.
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