Heat shock proteins as suppressors of accumulation of toxic prefibrillar intermediates and misfolded proteins in neurodegenerative diseases.

The most characteristic feature of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, is the occurrence of extra- or intracellular fibrillar aggregates containing misfolded proteins with beta-sheet conformation. These aggregates are composed of distinct proteins in each neurodegenerative disease. However, mutations in genes encoding major constituents of aggregates, such as Abeta, tau, alpha-synuclein, SOD1 and huntingtin, have been identified to causally associate with familial forms of the diseases. Biochemical studies demonstrate that these mutant and some wild-type proteins tend to be misfolded or form aggregates. It has been proposed that these diseases are caused by a common mechanism involving misfolded proteins that trigger a toxic cascade leading to neuronal degeneration. This hypothesis is the basis of the therapeutic potential of heat shock proteins (HSPs), which prevent protein misfolding and aggregation. Transgenic animal models of the diseases have demonstrated that induction or overexpression of HSPs can suppress neuronal dysfunction and degeneration. Do the results promise clinical success for HSP-based therapy in neurodegenerative diseases? Recent findings regarding the pathogenic species generated during fibril formation have highlighted some of the beneficial and problematic aspects of HSP-based therapy. In this review, we focus on the pathogenic role of prefibrillar intermediates, including soluble oligomers and protofibrils, on neurodegeneration, and the relationship between prefibrillar intermediates and the proteins targeted by HSPs. We discuss in vitro and in vivo experimental data showing that HSPs counteract disease progression by acting as suppressors of toxic prefibrillar intermediates and toxic misfolded proteins in neurodegenerative diseases.