Repeat-Associated Non-ATG Translation in Neurological Diseases

Abstract

More than 40 different neurological diseases are caused by microsatellite repeat expansions that locate within translated or untranslated gene regions, including 5' and 3' untranslated regions (UTRs), introns, and protein-coding regions. Expansion mutations are transcribed bidirectionally and have been shown to give rise to proteins, which are synthesized from three reading frames in the absence of an AUG initiation codon through a novel process called repeat-associated non-ATG (RAN) translation. RAN proteins, which were first described in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1), have now been reported in a growing list of microsatellite expansion diseases. This article reviews what is currently known about RAN proteins in microsatellite expansion diseases and experiments that provide clues on how RAN translation is regulated.

Figure 1.

Bidirectional transcription and repeat-associated non-ATG (RAN) translation in repeat expansion disorders. Antisense transcripts and RAN proteins have been observed in a growing number of microsatellite expansions, including spinocerebellar ataxia type 8 (SCA8), myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), fragile X tremor ataxia syndrome (FXTAS), C9ORF72 amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), Huntington disease (HD), and spinocerebellar ataxia type 31 (SCA31). RAN proteins that have been identified in various expansion diseases and confirmed in patient tissues are shown in red.

Figure 2.

Repeat-associated non-ATG (RAN) translation of CAG and CGG repeats. Model of RAN translation showing repeat-length dependence and preference for hairpin or secondary RNA structures. RAN translation can occur in multiple reading frames and, depending on the disease locus, at start sites upstream of the repeats or at multiple sites within the repeat tract. Experiments on CAG repeats suggest that translation initiation in the polyGln frame occurs upstream of the repeat tract, although initiation in the polyAla reading frame occurs throughout the repeat. Translation of FXTAS polyGly and polyAla have been shown to be cap-dependent and require eIF4E and eIF4A. RAN-TAFs, putative RAN-translation associated factors.