RNA-mediated toxicity in neurodegenerative disease

Abstract

Cellular viability depends upon the well-orchestrated functions carried out by numerous protein-coding and non-coding RNAs, as well as RNA-binding proteins. During the last decade, it has become increasingly evident that abnormalities in RNA processing represent a common feature among many neurodegenerative diseases. In "RNAopathies", which include diseases caused by non-coding repeat expansions, RNAs exert toxicity via diverse mechanisms: RNA foci formation, bidirectional transcription, and the production of toxic RNAs and proteins by repeat associated non-ATG translation. The mechanisms of toxicity in "RNA-binding proteinopathies", diseases in which RNA-binding proteins like TDP-43 and FUS play a prominent role, have yet to be fully elucidated. Nonetheless, both loss of function of the RNA binding protein, and a toxic gain of function resulting from its aggregation, are thought to be involved in disease pathogenesis. As part of the special issue on RNA and Splicing Regulation in Neurodegeneration, this review intends to explore the diverse RNA-related mechanisms contributing to neurodegeneration, with a special emphasis on findings emerging from animal models.

Keywords: Bidirectional transcription; Mouse models; Neurodegenerative diseases; RAN translation; RNA foci; RNA processing.

Fig. 1

Aberrant RNA mechanisms in neurodegeneration. (A) Bidirectional Transcription: schematic representation of ATXN8 and ATXN8OS with repeat expansions located in the open reading frame (ORF) or the 3′UTR region, respectively. The CAG/CTG trinucleotide expansions are transcribed from the sense and antisense strands, consequently encoding for polyalanine and polyglutamine tracts in SCA8 patients. (B) Repeat Associated Non-ATG translation (RAN translation): schematic representation of mutant DMPK in DM1. The repeat expansion is transcribed bidirectionally, and translation can be initiated in any reading frame of the CUG/CAG repeat expansion, consequently encoding for polyleucine, polycysteine, polyalanine, polyglutamine, and polyserine tracts. (C) Epigenetic changes leading to haploinsufficiency: schematic representation of FMR1 in FXS patients. (CGG)_≥200 repeats are methylated and CpG islands encompassing the region are hypermethylated. This leads to histones H3 and H4 deacetylation and chromatin modification, consequently compressing the shape of the genomic material. Binding of methyl (CH₃) groups activates histone deacetylase complex, leading to gene silencing and haploinsufficiency. (D) RNA foci formation: schematic representation of the three transcripts and two protein isoforms of C9ORF72. Expanded GGGGCC repeats in C9ORF72 lead to decreased expression of transcript 2, and potentially RNA foci formation by transcripts 1 and 3. TDP-43 pathology is also present in C9ORF72 repeat expansion carriers affected with ALS and FTLD-TDP.