Huntingtin Spheroids and Protofibrils as Precursors in Polyglutamine Fibrilization;Inclusion Body Formation Reduces Levels of Mutant Huntingtin and the Risk of Neuronal Death;Pivotal Role of Oligomerization in Expanded Polyglutamine Neurodegenerative

摘要

Over the last two decades,the neurodegenerative disease field has witnessed impressive and unexpected developments in our understanding of the molecular basis of neurodegeneration. One group of inherited neurological disorders,classified as the so-called CAG/polyglutamine repeat diseases,has played a pivotal role in this process. The CAG/polyglutamine repeat diseases include nine disorders(spinal and bulbar muscular atrophy,Hunting-ton disease,dentatorubral pallidoluysian atrophy,and spinocerebellar ataxia types 1,2,3,6,7,and 17)caused by expansion of tandem CAG repeats in the coding regions of nine evolutionarily and functionally unrelated proteins. As soon as the first set of CAG/polyglutamine repeat disease genes were identified more than a decade ago,it became clear that production of an excessively elongated glutamine tract was a shared feature of disease pathogenesis in the different disorders.