Maladies par expansion de polyglutamine: Données moléculaires et physiopathologiques

Abstract

Over the past ten years, a growing number of hereditary neurodegenerative diseases have been associated with the expansion of an unstable trinucleotide CAG repeat coding for a polyglutamine tract in the respective protein. To date, this type of mutation have been found to cause nine neurodegenerative diseases: Huntington disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubropallidoluysian atrophy (DRPLA) and six types of spinocerebellar ataxias (SCA). Several common features characterize this group of diseases, especially dominant inheritance (except SBMA) and anticipation (earlier age at onset and more rapid disease progression in successive generations). Expanded polyglutamine tract renders the protein toxic and leads to aggregation in cells. These aggregates stain positively for ubiquitin, chaperons and proteasome, providing evidence that there are features common to the pathogenesis of these disorders. In this review, we summarize the model systems that have given insights into pathogenesis. Progress in the development of cellular and animal models provide resources for studying the disease mechanism and will be useful for screening and evaluating possible therapeutic strategies.