Polyglutamine neurodegeneration: protein misfolding revisited

Abstract

Polyglutamine diseases are a major cause of neurodegeneration worldwide. Recent studies highlight the importance of protein quality control mechanisms in regulating polyglutamine-induced toxicity. Here we discuss a model of disease pathogenesis that integrates current understanding of the role of protein folding in polyglutamine disease with emerging evidence that alterations in native protein interactions contribute to toxicity. We also incorporate new findings on other age-related neurodegenerative diseases in an effort to explain how protein aggregation and normal aging processes might be involved in polyglutamine disease pathogenesis.

Figure 1. Possible cellular sequelae of expanded polyQ protein misfolding

PolyQ proteins, when expanded, are prone to misfold. HSF-1 can trigger the expression of certain chaperones, including Hsp70 and Hsp40, which help refold misfolded polyQ proteins. When misfolded polyQ monomers form oligomers, chaperones can help to dissociate them. Misfolded monomers can also form complexes with other proteins. These aberrant heteroprotein complexes may cause the affected proteins to adopt novel functions or alter their normal functions. Oligomers may also interact with cellular proteins to cause similar alterations in function, though currently there is no direct experimental evidence. Some protein quality control components, such as the TRiC chaperonin complex, may reduce the toxicity of oligomers by changing their size and conformation. Based on current evidence, we suggest misfolded, polyQ-expanded monomers and resultant oligomers display reactive, accessible polypeptide surfaces that cause neuronal dysfunction and ultimately cell death.