13 - Spinocerebellar ataxia type 1

Abstract

This chapter discusses the pathogenesis, pathology, and pathophysiology of spinocerebellar ataxia type 1 (SCA1), along with mechanisms of disease recovery. The clinical features seen in patients with SCA1 usually include ataxia, dysarthria, and bulbar dysfunction. SCA1 appears to have a defined neuropathological pattern that separates it from other dominantly inherited ataxias and from sporadic entities such as multiple system atrophy. The disease-causing mutation is expansion of an unstable CAG trinucleotide repeat within the coding region of the gene. Disease is caused by the expansion of this repeat producing an expanded tract of glutamine amino acids within the SCA1 gene product, ataxin-1. SCA1 pathogenesis is induced by some toxic function gained by the mutant polyglutamine protein as a result of the expanded glutamine tract. Polyglutamine expansion seems to cause mutant ataxin-1 to adopt an altered folding state, leading to its ubiquitination, aggregation, and resistance to proteasomal degradation. Over the course of the disease, the aggregated protein may in turn contribute to disease progression by altering the turnover of other critical proteins that may encumber the ubiquitin–proteasome system. The chapter also presents an experimental mouse model that examines the capacity of Purkinje neurons to recover from the adverse effects of ataxin-1. Results suggest that Purkinje cells have a sustained ability to recover from long-term effects of mutant ataxin-1. A therapeutic intervention targeted at reducing the expression of mutant ataxin-1 showed that SCA1 RNAi was effective in suppressing Purkinje cell pathology and neurological signs when SCA1 mice were injected with SCA1 RNAi at 7 weeks of age.