AI Article Synopsis
- Several neurodegenerative disorders, including ALS and SCA, are linked to non-coding nucleotide repeat expansions that can cause different pathogenic mechanisms.
- Gain-of-function mechanisms, primarily associated with toxic RNA expression and repeat-associated non-ATG products, are commonly identified, while loss-of-function mechanisms are also considered.
- The review discusses various non-coding repeat expansion disorders, particularly focusing on RNA toxicity pathways, with special attention to C9ORF72-linked ALS/FTD, highlighting research efforts to differentiate between RNA and RAN toxicity.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939197 | PMC |
| http://dx.doi.org/10.15252/embj.2018101112 | DOI Listing |
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