Polyglutamine (
polyQ) expansion mutation causes conformational,
neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. These diseases are characterized by the aggregation of misfolded
proteins, such as
amyloid fibrils, which are toxic to cells.
Amyloid fibrils are formed by a nucleated growth polymerization reaction. Unexpectedly, the critical nucleus of
polyQ aggregation was found to be a monomer, suggesting that the rate-limiting nucleation process of
polyQ aggregation involves the folding of mutated
protein monomers. The
monoclonal antibody 1C2 selectively recognizes expanded pathogenic and aggregate-prone
glutamine repeats in
polyQ diseases, including
Huntington's disease (HD), as well as binding to
polyleucine. We have therefore assayed the in vitro and in vivo aggregation kinetics of these monomeric
proteins. We found that the repeat-length-dependent differences in aggregation lag times of variable lengths of
polyQ and
polyleucine tracts were consistently related to the integration of the length-dependent intensity of anti-1C2 signal on soluble monomers of these
proteins. Surprisingly, the correlation between the aggregation lag times of
polyQ tracts and the intensity of anti-1C2 signal on soluble monomers of huntingtin precisely reflected the repeat-length dependent age-of-onset of HD patients. These data suggest that the alterations in
protein surface structure due to
polyQ expansion mutation in soluble monomers of the mutated
proteins act as an
amyloid-precursor
epitope. This, in turn, leads to nucleation, a key process in
protein aggregation, thereby determining HD onset. These findings provide new insight into the gain-of-function mechanisms of
polyQ diseases, in which
polyQ expansion leads to nucleation rather than having toxic effects on the cells.