Toxic RNA in pathogenesis of human neuromuscular disorders

In the past decade, substantial progress has been made in our understanding of the molecular pathogenesis of microsatellite expansion disorders. Some of these diseases, such as myotonic dystrophy, fragile X-associated tremor/ataxia syndrome, spinocerebellar ataxias 8, 10, 12 and Huntington's disease-like 2, are caused by an increased number of tri-, tetra- or pentanucleotide repeats in noncoding regions of the mutated genes. An RNA gain-of-function mechanism has been proposed to explain how mutations in noncoding fragments of genes lead to a disease phenotype. A number of studies demonstrated that RNA molecules harboring long repeating sequences affect the metabolism of other RNAs via deregulation of RNA processing proteins. This chapter presents the current status of knowledge related to mechanisms of pathogenesis, involvement of RNA structures and specific RNA binding proteins in seven neurodegenerative diseases associated with an RNA gain-of-function mechanism. Potential therapeutic strategies directed towards toxic RNAs are also reviewed.