Lithium Therapy Improves Neurological Function and Hippocampal Dendritic Arborization in a Spinocerebellar Ataxia Type 1 Mouse Model

Kei Watase,Huda Y Zoghbi,Jennifer R Gatchel,Yaling Sun,Harry T Orr,Hidehiro Mizusawa,Ronald Richman,Richard Atkinson,Steven E Hyman,Chad Shaw,Effat Emamian

doi:10.1371/journal.pmed.0040182

Abstract

BackgroundSpinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction. Caused by an expanded polyglutamine tract in ataxin 1 (ATXN1), SCA1 pathogenesis involves a multifactorial process that likely begins with misfolding of ATXN1, which has functional consequences on its interactions, leading to transcriptional dysregulation. Because lithium has been shown to exert neuroprotective effects in a variety of conditions, possibly by affecting gene expression, we tested the efficacy of lithium treatment in a knock-in mouse model of SCA1 (Sca1154Q/2Q mice) that replicates many features of the human disease.Methods and Findings Sca1154Q/2Q mice and their wild-type littermates were fed either regular chow or chow that contained 0.2% lithium carbonate. Dietary lithium carbonate supplementation resulted in improvement of motor coordination, learning, and memory in Sca1154Q/2Q mice. Importantly, motor improvement was seen when treatment was initiated both presymptomatically and after symptom onset. Neuropathologically, lithium treatment attenuated the reduction of dendritic branching in mutant hippocampal pyramidal neurons. We also report that lithium treatment restored the levels of isoprenylcysteine carboxyl methyltransferase (Icmt; alternatively, Pccmt), down-regulation of which is an early marker of mutant ATXN1 toxicity.ConclusionsThe effect of lithium on a marker altered early in the course of SCA1 pathogenesis, coupled with its positive effect on multiple behavioral measures and hippocampal neuropathology in an authentic disease model, make it an excellent candidate treatment for human SCA1 patients.

Highlights

Spinocerebellar ataxia type 1 (SCA1) is one of nine known dominantly inherited neurodegenerative disorders caused by the expansion of a CAG repeat that encodes polyglutamine in the respective disease protein [1]
We report that lithium treatment restored the levels of isoprenylcysteine carboxyl methyltransferase (Icmt; alternatively, Pccmt), down-regulation of which is an early marker of mutant ataxin 1 (ATXN1) toxicity
Emamian et al [7] demonstrated that serine 776 (S776) in ataxin 1 (ATXN1) is essential for its pathogenicity in transgenic mice; Chen et al [8] showed that phosphorylation of this residue by Akt enables 14-3-3 to interact with and stabilize ATXN1

Summary

Introduction

Spinocerebellar ataxia type 1 (SCA1) is one of nine known dominantly inherited neurodegenerative disorders caused by the expansion of a CAG repeat that encodes polyglutamine in the respective disease protein [1]. Because lithium has been shown to exert neuroprotective effects in a variety of conditions, possibly by affecting gene expression, we tested the efficacy of lithium treatment in a knock-in mouse model of SCA1 (Sca1154Q/2Q mice) that replicates many features of the human disease. SCA1 is a ‘‘polyglutamine disease,’’ a group of neurodegenerative disorders in which an abnormal protein (a different one for each disease) containing a long stretch of glutamine forms nuclear inclusions (insoluble lumps of protein) in neurons that, possibly by trapping essential proteins, cause neuronal death. In SCA1, the abnormal protein is ataxin 1, which is made in many neurons including the cerebellar neurons (Purkinje cells) that coordinate movement

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