New Targets for Therapy in Polyglutamine (polyQ) Expansion Diseases

The polyglutamine (polyQ) repeat disorders are a family of inherited disorders characterized by progressive neurodegeneration, as well as the formation of intracellular protein aggregates. Huntington's disease (HD) is the most prevalent disorder in the family of polyQ diseases. This family includes nine other neurodegenerative disorders: Dentatorubral-pallidoluysian atrophy (DRPLA), Bulbo-Spinal Muscular Atrophy (BSMA) and Spinocerebellar ataxia (SCA) types 1-3, 6, 7, 12 and 17. Each disease is caused by the expansion of a tract of repeated CAG triplet in a distinct gene, causing transcription of proteins with lengthened polyQ repeats. Although mutations occur frequently in a ubiquitously expressed gene, neurodegeneration occurs in a specific cell type. The mutant proteins involved in polyQ disease are unrelated and they share only the glutamine extension. As for the pathogenic mechanism by wich the repeat expansion leads to the disease, major models include a loss of function of the gene and a gain of function by the mutant RNA transcript or protein product. Indeed, altered function in the ubiquitin-proteasome system (UPS), endoplasmic reticulum (ER) and mitochondria function, as well as a primary failure in autophagy has been demonstrated. However, the pathogenic mechanism varies from one disease to another, depending on the motif, length, and intragenic location of the repeat. Understanding the molecular mechanisms of repeat instability and pathogenic process is not only of scientific interest but also essential for the development of rational treatment of these diseases.