Neurodegenerative Diseases and RNA-Mediated Toxicity

Several neurodegenerative diseases are associated with the expansion of unstable DNA repeats. While some of these repeats exist in the coding region of genes and result in a toxic gain of function at the protein level, other repeats are noncoding, leading to the hypothesis that pathogenesis could originate from the effects of a mutant RNA. A common theme in these RNA-mediated diseases is the accumulation of the mutant RNA transcripts into foci, and it has long been hypothesized that these accumulations sequester and subsequently inhibit RNA-binding proteins, resulting in defects in RNA processing. To complicate matters, many of these repeat loci are bidirectionally transcribed, resulting in antisense repeat transcripts that are also toxic. Furthermore, the discovery of repeat-associated non-ATG (RAN) translation allows the expression of a mutant RNA to also result in the accumulation of toxic proteins. This chapter summarizes how these different mechanisms relate to specific neurodegenerative diseases.