Journal
CHEMISTRY & BIOLOGY
Volume 19, Issue 10, Pages 1340-1353Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2012.07.013
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Funding
- Neurosearch A/S
- NIH [R01NS056224, R01NS38082, R01NS074376]
- Welch Foundation [I-1754]
- Russian Ministry of Science [14.740.11.0924]
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Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by a polyglutamine expansion within the Ataxin-2 (Atxn2) protein. Purkinje cells (PC) of the cerebellum fire irregularly and eventually die in SCA2. We show here that the type 2 small conductance calcium-activated potassium channel (SK2) play a key role in control of normal PC activity. Using cerebellar slices from transgenic SCA2 mice we demonstrate that SK channel modulators restore regular pacemaker activity of SCA2 PCs. Furthermore, we also show that oral delivery of a more selective positive modulator of SK2/3 channels (NS13001) alleviates behavioral and neuropathological phenotypes of aging SCA2 transgenic mice. We conclude that SK2 channels constitute a therapeutic target for SCA2 treatment and that the developed selective SK2/3 modulator NS13001 holds promise as a potential therapeutic agent for treatment of SCA2 and possibly other cerebellar ataxias.
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