Chaperones and Polyglutamine Expansion Disorders

Abstract

Polyglutamine expansion disorders are caused by the misfolding of proteins with abnormally long polyglutamine regions. This misfolding produces toxicity and leads to the dysfunction and ultimately to the demise of neurons in affected individuals. The molecular basis for polyglutamine toxicity is unclear and the number and complexity of documented cellular pathways involved in polyglutamine expansion disorders is daunting. However, the use of effective experimental model systems is rapidly advancing our understanding of polyglutamine misfolding and the cellular factors that govern the related toxicity. Molecular chaperones, the central regulators of cellular protein quality control, improve polyglutamine misfolding and hence ameliorate polyglutamine toxicity. Additionally, polyglutamine expansion proteins overwhelm molecular chaperones and thereby reduce their capacity to execute protein quality control. Hence, dysfunctional cellular protein quality control presents a very basic and fundamental problem of protein misfolding and therefore of polyglutamine toxicity. Thus, the elucidation of the interplay between polyglutamine expansion proteins and molecular chaperones contributes profoundly to our understanding of polyglutamine expansion disorders and offers great promise for developing effective therapeutic strategies in the treatment of these devastating maladies