ABSTRACT Trinucleotide repeat expansions have been identified as being responsible for 10 of the autosomal dominant hereditary ataxias. Among them, eight have expansion of the repeat sequences cytosine-adenine-guanosine (CAG), and the trinucleotide repeat CAG is in the coding region, resulting in an expansion of a normal polyglutamine (polyQ) tract in the translated protein. While the mechanisms of selective neurotoxicity are still poorly understood, all the polyQ diseases present similarities that suggest overlap in the mechanism of pathogenesis and potentially similar therapeutic strategies. The dominant inheritance pattern, late onset of symptoms, and similar clinical presentation in homozygote and heterozygote patients support a toxic gain-of-function of the corresponding protein. Currently hypothesized mechanisms of cell death in polyQ disorders include abnormal protein aggregation, apoptosis, excitotoxicity, impaired energy metabolism, defective transcription, impaired axonal transport, trophic factor starvation, proteasome impairment, and chaperone dysfunction. While each of these processes is detrimental to cell function, it may be that a combination of these phenomena is responsible for cell death. Increasing insights into the pathophysiology of repeat expansion disorders have led to the development of new therapeutic candidates that may enter the clinic in the near future. Several compounds acting on different cellular pathways have been shown to be beneficial in preclinical studies that have set the stage for future clinical trials. It is unlikely that any one therapy will be optimal, but rather treating several facets of the pathogenic process may be necessary to bring about a favorable clinical outcome. Moreover, use of several compounds may offer synergistic effects that allow lower doses of each drug, thereby reducing the toxicity potential of any one drug. In this regard, a thorough study of combination therapies is required both in vitro and in vivo in various SCA models. Additionally, cross model validation will help to prioritize which drug(s) to move forward into clinical trials.
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