Selective Positive Modulator of Calcium-Activated Potassium Channels Exerts Beneficial Effects in a Mouse Model of Spinocerebellar Ataxia Type 2

Abstract

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 novel selective positive modulator of SK2/3 channels (NS13001) alleviates behavioural and neuropathological phenotypes of aging SCA2 transgenic mice. We conclude that SK2 channels constitute a novel 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.

Targeting potassium channels to treat cerebellar ataxia

“…In this study, we illustrate that improving Purkinje neuron spiking indeed improves motor performance in the short‐term, an effect which has been previously illustrated using K Ca activators in a mouse model of SCA2 20. Motor dysfunction is likely not improved to wild‐type levels, however, as these compounds restore firing only with a greatly reduced firing frequency.…”

“…Previous studies have focused on restoring somatic spiking as an approach to improve motor function in mouse models of ataxia 2, 19, 20, 49. In this study, we illustrate that improving Purkinje neuron spiking indeed improves motor performance in the short‐term, an effect which has been previously illustrated using K Ca activators in a mouse model of SCA2 20.…”

“…Many SCAs are caused by conventional mutations in ion channel genes ( KCNMA1, KCNC3, KCND3, CACNA1A, CACNA1G, ITPR1, SCA8A, TRPC3 ),6, 11, 12, 13, 14, 15, 16, 17, 18 and alterations in ion channel function are secondary to disease‐causing mutations in several mouse models of spinocerebellar ataxia (SCA1, SCA2, SCA3, SCA6) 1, 2, 3, 4, 19. In mouse models of SCA, ion channel modulators correct irregular Purkinje neuron spiking and improve motor impairment 19, 20. Recently, clinical trials for the compound riluzole have demonstrated therapeutic promise for the treatment of several forms of SCA 21, 22.…”

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

“…Abnormal bursting behavior of Purkinje neurons has been identified in a mouse model of SCA2, and it was found that this bursting could be corrected with the application of a small conductance calcium-activated potassium (SK) channel activator. The same SK channel activator also alleviates behavioral and neuropathological changes in SCA2 mice [83]. Taken together, these data support a role for altered excitability in promoting pathology in SCA2.…”

Pharmacological gating modulation of small- and intermediate-conductance Ca2+-activated K+channels (KCa2.x and KCa3.1)

“…54,55 While this effect is straightforward to rationalize from the mode-of-action of positive modulators, it is less clear why CyPPA, NS13001, and SKA-31 exert positive effects in rodent models of spinocerebellar ataxias (SCA2 and SCA3), which are due to gain-offunction toxicity caused by glutamine prolongation of ataxins. 41,56 One possibility is that diseased Purkinje cells -maybe independently of the molecular cause -go through phases where the highly regulated pacemaker firing is lost, for example through changes in climbing fiber input or denervation, 57,58 leading to excessive endogeneous burst firing, depolarization block, and Ca 2C overload, which may contribute to accelerated cell death.…”