Chapter 25 - Spinocerebellar ataxia type 1

Abstract

Spinocerebellar ataxia type 1 (SCA1) is one out of nine polyglutamine diseases, a group of late-onset neurodegenerative diseases present only in humans. SCA1, the first autosomal dominant cerebellar ataxia (ADCA) to be genetically characterized, is caused by the expansion of a CAG triplet repeat located in the N-terminal coding region of the disease-causing gene ATX1 located on chromosome 6p23: the mutation results in the production of a mutant protein, dubbed ataxin-1, with a longer-than-normal polyglutamine stretch. The predominant effect of the mutation is thought to be a toxic gain-of-function of the aberrant protein, and longer expansions are associated with earlier onset and more severe disease in subsequent generations. The most common presentation of SCA1 is dominant ataxia 'plus', characterized by cerebellar dysfunctions variably associated with slow saccades, ophthalmoplegia, pyramidal and extrapyramidal features, mild to moderate dementia, amyotrophy, and peripheral neuropathy. Its diagnostic pathological feature is olivopontocerebellar atrophy and degeneration predominantly affects the Purkinje cells and the dentate nuclei of the cerebellum. Pathogenesis is mainly attributed to the toxic effect of mutant ataxin-1, which localizes into the nucleus and, through restricted and aberrant protein-protein interactions, causes putative dysfunctional gene transcription in target cells which leads to late-onset cell dysfunction and death.