Polyglutamine diseases are a group of inherited neurodegenerative disorders that are caused by an abnormal expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in the protein-coding region of the respective disease genes. To date, nine polyglutamine diseases are known, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy and six forms of spinocerebellar ataxia. These diseases share a salient molecular pathophysiology including the aggregation of the mutant protein followed by the disruption of cellular functions such as transcriptional regulation and axonal transport. The intraneuronal accumulation of mutant protein and resulting cellular dysfunction are the essential targets for the development of disease-modifying therapies, some of which have shown beneficial effects in animal models. In this review, the current status of and perspectives on therapy development for polyglutamine diseases will be discussed.
Keywords: Huntington’s disease; autophagy; biomarker; disease-modifying therapy; molecular chaperone; polyglutamine; spinal and bulbar muscular atrophy; spinocerebellar ataxia; translational research; ubiquitin–proteasome.