Mechanisms of cell death in polyglutamine expansion diseases.

Abnormal protein aggregation is a hallmark of many neurodegenerative diseases. However, the mechanism by which protein aggregates induce neurodegneration remains controversial. Recently proposed mechanisms of neuronal death in polyglutamine expansion diseases include activation of caspases and associated cell death pathways, interference with transcriptional regulation, downregulation of survival pathways and obstruction of axonal transport. Because the expression of expanded polyglutamine in selected neuronal populations can adversely affect multiple aspects of neuronal survival and function, we propose that effective therapeutic approaches might have to target the upstream mechanism of neurotoxicity by selectively inhibiting the formation of intraneuronal aggregates and increasing the degradation of mutant proteins.