[Therapeutic strategies for the polyglutamine diseases]

The polyglutamine diseases are a group of nine inherited neurodegenerative diseases including Huntington disease, spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17, dentatorubral pallidoluysian atrophy, and spinobulbar muscular atrophy, which are caused by an abnormal expansion of the CAG repeat encoding a polyglutamine stretch in each unrelated disease-causing gene. In the pathogenesis of the polyglutamine diseases, expansion of the polyglutamine stretch causes misfolding and conformational alterations of the disease-causing proteins, leading to pathogenic protein-protein interactions including aggregate formation, and subsequently resulting in their deposition as inclusion bodies in affected neurons. Expression of these expanded polyglutamine proteins has been reported to impair protein degradation, transcriptional regulation, axonal transport, mitochondrial function, etc., which eventually result in neurodegeneration. Currently, a wide variety of research towards establishing therapies targeting each step in the pathogenesis of the polyglutamine diseases is in progress, which includes suppressing mutant gene expression by RNAi, inhibiting protein misfolding/aggregation, promoting protein degradation, activating transcription, activating mitochondrial function, inhibiting neuronal cell death, and neuroprotection by neurotrophic factors. Standardized validation of these preclinical studies and development of sensitive biomarkers for evaluation of therapeutic efficacy in clinical trials will be necessary for development of drugs for the polyglutamine diseases.