Abstract
Several neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia (SCA) are caused by non‐coding nucleotide repeat expansions. Different pathogenic mechanisms may underlie these non‐coding repeat expansion disorders. While gain‐of‐function mechanisms, such as toxicity associated with expression of repeat RNA or toxicity associated with repeat‐associated non‐ATG (RAN) products, are most frequently connected with these disorders, loss‐of‐function mechanisms have also been implicated. We review the different pathways that have been linked to non‐coding repeat expansion disorders such as C9ORF72‐linked ALS/frontotemporal dementia (FTD), myotonic dystrophy, fragile X tremor/ataxia syndrome (FXTAS), SCA, and Huntington's disease‐like 2. We discuss modes of RNA toxicity focusing on the identity and the interacting partners of the toxic RNA species. Using the C9ORF72 ALS/FTD paradigm, we further explore the efforts and different methods used to disentangle RNA vs. RAN toxicity. Overall, we conclude that there is ample evidence for a role of RNA toxicity in non‐coding repeat expansion diseases.
Highlights
Non-coding repeat expansion disorders Several neurodegenerative disorders are caused by a non-coding repeat expansion and are referred to as “non-coding repeat expansion disorders”
Detection of dipeptide repeat proteins” (DPRs), and presence of C9 amyotrophic lateral sclerosis (ALS) hallmarks in sense and antisense in vivo models expressing non-ATG C9ORF72 repeat constructs
(1) Compromised function of nucleolin (NCL) might induce nucleolar stress. (2) mRNA might be retained in the nucleus due to repeat RNA-induced nuclear accumulation of mRNA export proteins like PABPC. (3) Splicing might be disturbed due to compromised function of several splicing factors like HNRNPH. (4) Nucleocytoplasmic transport might be directly disturbed by repeat RNA via RanGAP1 dysfunction
Summary
Non-coding repeat expansion disorders Several neurodegenerative disorders are caused by a non-coding repeat expansion and are referred to as “non-coding repeat expansion disorders”. ALS amyotrophic lateral sclerosis ASO antisense oligonucleotide DPR dipeptide repeat protein ELISA enzyme-linked immunosorbent assay FTD frontotemporal dementia FTLD frontotemporal lobe degeneration FXTAS fragile X tremor ataxia syndrome HDL-2 Huntington’s disease-like 2 hnRNP heterogeneous nuclear ribonucleoprotein HRE hexanucleotide repeat expansion iMNs induced motor neurons mRNP messenger ribonucleoprotein PET positron emission tomography RAN repeat-associated non-ATG RBP RNA-binding protein rRBP repeat RNA-binding protein SCA spinocerebellar ataxia UPS ubiquitin-proteasome system UTR untranslated region defective transcription (e.g., abortion), or increased mRNA degradation of the host gene (Todd et al, 2010; Haeusler et al, 2014). Data support the notion that GA can be toxic, while GP and PA are probably harmless (at least in the currently available disease models) Despite these in vitro and in vivo findings, it remains to be determined whether DPRs contribute to the pathogenesis of C9 ALS/FTD in humans. In C9 ALS/FTD post-mortem brain tissue, C9ORF72 transcript levels are decreased by 50%
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