BioCentury
ARTICLE | Distillery Therapeutics

Therapeutics: Sirtuin 1 (SIRT1); ataxin 3 (ATXN3)

May 26, 2016 7:00 AM UTC

Patient sample and mouse studies suggest promoting SIRT1 activity could help treat spinocerebellar ataxia type 3 (SCA3), a neurodegenerative disease caused by mutant ATXN3 encoding polyglutamine repeats. Levels of SIRT1 were lower in fibroblasts from SCA3 patients than in fibroblasts from healthy volunteers. In a mouse model of SCA3 that expressed polyglutamine repeats in Purkinje cells, a calorie-restricted diet increased cerebellar levels of SIRT1, cerebellar volume, motor coordination, balance, muscle strength and gait and decreased cerebellar atrophy compared with normal diet. Also in the model, the SIRT1 activator resveratrol increased motor coordination, balance and gait compared with vehicle. In a second mouse model of SCA3 that expressed mutant ATXN3, viral-vector mediated expression of human SIRT1 in the brain decreased accumulation and aggregation of mutant ATXN3, cerebellar atrophy and levels of proinflammatory cytokines compared with control vector. Next steps could include identifying and testing other SIRT1 activators in the models of SCA3. ...