Expansion of an unstable translated CAG repeat found in different disease genes results in long tracts of poly-glutamines in specific encoded proteins, and has been found to cause at least nine different neurodegenera-tive diseases including spinal and bulbar muscular atrophy, Huntington's disease, and six spinocerebellar ataxias. These diseases involve specific groups of neurones and have distinct clinical features (see Fig. 7.8). Disease is associated primarily with gain of function. For example, null mice for ataxin-1, the protein bearing a polyglutamine repeat expansion in spinocerebellar ataxia type 1 (SCA1) (Box 7.11), do not develop features of the disorder (Matilla et al. 1998), while transgenic and knock-in animal models expressing full length proteins containing long tracts of glutamine repeats do (Watase et al. 2002). Polyglutamine diseases are dominantly inherited and a 'toxic' change in the protein conferred by the glutamine expansion is postulated. A change in protein conformation and accumulation and the formation of insoluble aggregates at nuclear and/or cytoplasmic locations are often seen. Overexpression of the protein without repeat expansion is noted to result in mild disease in some animal models, for example with wild type ATXN1 in the mouse and fly, consistent with the repeat expansion enhancing existing interactions and resulting in gain of function (Fernandez-Funez et al. 2000).
Expansion of the glutamine tract is necessary but not sufficient for pathology to result; other sequences are also important. In SCA1, for example, ataxin-1 containing the polyglutamine repeat expansion does not lead to cerebellar degeneration in the presence of a specific serine to alanine substitution (at residue 776) which prevents phosphorylation (Emamian et al. 2003). The situation is complex and may not be restricted to gain of function: in SCA1, there is evidence that the polyglutamine expansion in ATXNT, in the presence of phos-phorylated serine 776, both enhances the formation of a protein complex with an RNA-binding motif protein 17 (RBM17) promoting neuropathology, and represses the formation and function of a protein complex containing the transcriptional repressor protein capicua (which has been associated with protection from toxicity associated with ataxin-1) (Lam et al. 2006; Lim et al. 2008). It may be, therefore, that SCA1 derives from both gain of function and partial loss of function, and that this is specific to particular protein interactions. The interaction with
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