Critical nucleus size for disease-related polyglutamine aggregation is repeat length dependent

Since polyglutamine (polyQ) aggregate formation has been implicated as playing an important role in expanded CAG repeat diseases, it is important to understand the biophysics underlying the initiation of aggregation. Previously we showed that relatively long polyQ peptides aggregate by nucleated growth polymerization and a monomeric critical nucleus. We show here that, over a short repeat length range from Q(26) to Q(23), the size of the critical nucleus for aggregation increases from monomeric to dimeric to tetrameric. This variation in nucleus size suggests a common duplex anti-parallel β-sheet framework for the nucleus, and further supports the feasibility of an organized monomeric aggregation nucleus for longer polyQ repeat peptides. The data also suggest that a change in aggregation nucleus size may play a role in the pathogenicity of polyQ expansion in this series of familial neurodegenerative diseases.