Pathophysiology of SCA1

Abstract

In 1991, a novel mutational mechanism in human genetics was discovered: the expansion of an unstable trinucleotide repeat (Fu et al., 1991; La Spada et al., 1991). To date, trinucleotide repeat expansions have been found to be associated with 16 neurological disorders. Although the sequence of the unstable repeat and its location within the affected gene varies among these disorders, by far the largest category of disorders are those in which the neurodegenerative disease results from the expansion of a CAG repeat. Because the CAG tract is located in the coding region of each gene and encodes a polyglutamine stretch in each respective protein, these disorders are often designated as polyglutamine diseases (Ross, 1997). The eight polyglutamine repeat diseases currently include Kennedy disease or spinobulbar muscular atrophy (SBMA), Huntington disease (HD), and the spinocerebellar ataxias (SCA1, SCA2, SCA3, Machado-Joseph disease [MJD], SCA6, and SCA7), including dentatorubropallidoluysian atrophy (DRPLA). Except for Kennedy disease (SBMA), these neurodegenerative disorders are dominantly inherited. All eight polyglutamine disorders are progressive, often with an onset in mid-life with an increase in neuronal dysfunction and eventual neuronal loss 10–20 yr after onset. Other features that characterize this group of diseases are (1) an inverse relationship between the number of CAG repeats on expanded alleles and age of onset and severity of disease and (2) an intergenerational instability that leads to repeat expansions and earlier age of onset and more rapid disease progression in affected offspring of affected parents. Most interesting, despite the widespread expression of the relevant protein throughout the brain and other tissues, only a subset of neurons that is unique to each disease appears to be vulnerable to the mutation in each of these diseases. This review focuses on one of these polyglutamine disorders, spinocerebellar ataxia type 1 (SCA1). The reader is referred to other chapters for reviews on some of the other polyglutamine disorders: Huntington disease (Chapters 9–11 and 13), Kennedy disease (Chapter 14), and SCA3/MJD (Chapter 15).