Y. Trottier et al., POLYGLUTAMINE EXPANSION AS A PATHOLOGICAL EPITOPE IN HUNTINGTONS-DISEASE AND 4 DOMINANT CEREBELLAR ATAXIAS, Nature, 378(6555), 1995, pp. 403-406
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).