Conformational diseases: structural studies of aggregation of polyglutamine proteins

Protein misfolding and aggregation into insoluble amyloid deposits are often associated with neurodegenerative disorders. In particular, the polyglutamine (polyQ) diseases are inherited disorders triggered by the expansion of the polyQ tract over its physiological length in the involved protein. The molecular mechanism of aggregation from the native protein into amyloids involves several steps including protein misfolding, aggregation into oligomers, which seems to be the most toxic species, and, finally rearrangements into mature fibrils. In the present contribution, we review studies, integrating computational and experimental approaches, of polyQ proteins, as well as of the details of the complicate aggregation mechanisms in which aberrant form of polyQ proteins are involved. These aspects are of crucial relevance for a complete understanding of the onset of polyQ conformational diseases and can also shed light on putative therapeutic targets and future development of aggregation inhibitors.