Ion channel dysfunction in cerebellar ataxia

Abstract

Cerebellar ataxias constitute a heterogeneous group of disorders that result in impaired speech, uncoordinated limb movements, and impaired balance, often ultimately resulting in wheelchair confinement. Motor dysfunction in ataxia can be attributed to dysfunction and degeneration of neurons in the cerebellum and its associated pathways. Recent work has suggested the importance of cerebellar neuronal dysfunction resulting from mutations in specific ion-channels that regulate membrane excitability in the pathogenesis of cerebellar ataxia in humans. Importantly, even in ataxias not directly due to ion-channel mutations, transcriptional changes resulting in ion-channel dysfunction are tied to motor dysfunction and degeneration in models of disease. In this review, we describe the role that ion-channel dysfunction plays in a variety of cerebellar ataxias, and postulate that a potential therapeutic strategy that targets specific ion-channels exists for cerebellar ataxia.

Keywords: Channel activator; Electrophysiology; Ion channel; Potassium channel; Purkinje neuron; Spinocerebellar ataxia.

Figure 1. Ion-channel dysfunction is associated with spinocerebellar ataxia in humans and rodent models

Ion-channels, which are displayed in the cell membrane, and other ion-channel associated proteins causing spinocerebellar ataxia in humans or rodent models of disease, are shown. SCAs associated with each protein are listed above or under each protein. Mutations which result in an SCA channelopathy are listed in red. Ion-channel dysfunction in mouse models of polyQ SCA are listed in blue. Dravet syndrome, a severe myoclonic epilepsy of infancy which can result in ataxia, is shown in green. Dashed arrows signify a protein-protein interaction. Solid arrows signify the direction of ion movement upon channel activation. Abbreviations: SCA, spinocerebellar ataxia; polyQ, polyglutamine; Na_v, voltage-gated sodium channel; K_v, voltage-gated potassium channel; Ca_v, voltage-gated calcium channel; BK, large conductance calcium-activated potassium channel; TRPC3, transient receptor potential cation channel type 3; mGluR1, metabotropic glutamate receptor type 1; FGF14, fibroblast growth factor 14; ITPR1, inositol 1,4,5 trisphosphate receptor type 1; PLC, phospholipase C; Na⁺, sodium ion; K⁺, potassium ion; Ca²⁺, calcium ion.