Chemistry & Biology
Volume 19, Issue 10, 26 October 2012, Pages 1340-1353
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Article
Selective Positive Modulator of Calcium-Activated Potassium Channels Exerts Beneficial Effects in a Mouse Model of Spinocerebellar Ataxia Type 2

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Summary

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.

Highlights

► SK2 potassium channels control pacemaker activity of cerebellar Purkinje cells (PC) ► NS13001 was identified as potent positive modulator of type SK2/3 channels ► Oral delivery of NS13001 alleviated symptoms of transgenic mice model of SCA2 ataxia ► NS13001 holds promise as a potential therapeutic agent for treatment of ataxia

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These authors contributed equally to this work

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Present address: Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark