![]() ![]() Molecular chaperones, which are sequestered in inclusion bodies, suppress neurodegeneration in several animal models of protein misfolding diseases, including HD ( 14, 15). ![]() The molecular mechanism for this misfolding is not clear, but A11 seems to recognize a structural motif that is exposed only in oligomers and not in the native structure, random coil monomers, or mature fibrils ( 13). Thus, the misfolding of disease proteins to a similar oligomeric conformation might contribute to their toxicity. Many disease-causing proteins form toxic oligomers that react in a conformation-dependent manner with A11, an antibody that neutralizes their toxicity in cell-based assays ( 12). Therefore, only subsets of such structures might be most biologically active. However, oligomers are also highly heterogeneous in size, stability, and solubility ( 2). Importantly, mutant htt fragments and synthetic polyQ peptides form oligomers in a polyQ length-dependent manner in vitro and in vivo, consistent with a causative role for these structures in HD pathogenesis ( 2). In a cellular model of HD, the survival rate of cells is greater in the presence of inclusion bodies that contain fibrils than in their absence ( 11). Consistent with this scenario, in cell and mouse models of HD, misfolded species of mutant htt in a diffuse fraction impair cellular machinery before fibrils accumulate ( 8, – 10). More recent studies indicate that mutant htt and other disease-associated proteins with polyglutamine (polyQ) expansions also exist as smaller oligomers that have spherical, annular, and protofibrillar morphologies ( 5, – 7) that might be less energetically stable and more chemically reactive (and toxic) than fibrils. The assembly of mutant htt into amyloid-like fibrils was initially thought to be causally associated with the pathogenesis of HD ( 3, 4). Which of these structures, if any, mediate toxic gain-of-function protein interactions that cause neuronal dysfunction and cell death in HD is not well understood. 4 Recent studies suggest that mutant htt is a highly dynamic protein that adopts multiple misfolded monomeric and higher order conformations that exist in a dynamic equilibrium ( 1, 2). The accumulation of aggregated mutant htt in cytoplasmic and intranuclear inclusion bodies in neurons is a pathological hallmark of HD. ![]()
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