RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders

Wojciechowska, Marzena; Olejniczak, Marta; Galka-Marciniak, Paulina; Jazurek, Magdalena; Krzyzosiak, Wlodzimierz J.

A particular group of human neurological disorders is associated with expansions of simple repetitive elements within specific genes. This class comprises more than 20 diseases, which have been categorized into coding and noncoding repeat expansion disorders depending on the genetic location of their causative mutations (1) (2) (3) . The toxicity of the coding repeats located within ATG-initiated open reading frames (ORFs) is typically governed via a protein gainof-function mechanism. This mode of repeat toxicity is found in numerous disorders, including Huntington's disease (HD), spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, 8 and 17, dentatorubral-pallidoluysian atrophy (DRPLA) and spinal and bulbar muscular atrophy (SBMA), in which the expression of exonic CAG repeat expansions gives rise to polyglutamine (polyGln)-rich proteins that adversely affect various cellular functions (3) . However, the toxicity of coding CAG repeats can also be exerted on the transcript level via an RNA gain-of-function mechanism that was initially described for the noncoding repeat expansion disorder myotonic dystrophy type 1 (DM1) (4) (5) (6) (7) (8) . Also Fragile X-associated tremor ataxia syndrome (FXTAS), myotonic dystrophy type 2 (DM2), SCA31, SCA10, SCA8 and, most recently, amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD) have been shown to exhibit toxicity via a mutant transcript gain-of-function mechanism. In these diseases, the expression of transcripts harboring expansions of particular repeats leads to the formation of nuclear RNA foci that sequester specific RNA-binding proteins, resulting in a loss of their normal function (9) (10) (11) .