POLYGLUTAMINE EXPANSION AS A PATHOLOGICAL EPITOPE IN HUNTINGTONS-DISEASE AND 4 DOMINANT CEREBELLAR ATAXIAS

A POLYGLUTAMINE expansion (encoded by a CAG repeat) in specific protei ns causes neurodegeneration in Huntington's disease (HD) and four othe r disorders(1-6), by an unknown mechanism thought to involve gain of f unction or toxicity of the mutated protein(7,8). The pathological thre shold is 37-40 glutamines in three of these diseases, whereas the corr esponding normal proteins contain polymorphic repeats of up to about 3 5 glutamines(1-3). The age of onset of clinical manifestations is inve rsely correlated to the length of the polyglutamine expansion. Here we report the characterization of a monoclonal antibody that selectively recognizes polyglutamine expansion in the proteins implicated in HD a nd in spinocerebellar ataxia (SCA) 1 and 3. The intensity of signal de pends on the length of the polyglutamine expansion, and the antibody a lso detects specific pathological proteins expected to contain such ex pansion, in SCA2 and in autosomal dominant cerebellar ataxia with reti nal degeneration, whose genes have not yet been identified(9-13).