RNA Helicases in Microsatellite Repeat Expansion Disorders and Neurodegeneration.

Front Genet

Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.

Published: May 2022

AI Article Synopsis

  • Short repeated sequences of nucleotides, known as microsatellite expansions, are linked to over 50 neurodegenerative disorders that, while rare, significantly impact healthcare systems, especially as the population ages.
  • The pathogenic mechanisms behind these diseases involve complex interactions leading to neuronal injury, with RNA and protein dysfunction being key players in disease progression.
  • The review will focus on the roles of specific RNA helicases in modifying the translation of toxic proteins in certain microsatellite expansion disorders, while also highlighting the challenges and potential for targeting these helicases in treatment development.

Article Abstract

Short repeated sequences of 3-6 nucleotides are causing a growing number of over 50 microsatellite expansion disorders, which mainly present with neurodegenerative features. Although considered rare diseases in relation to the relatively low number of cases, these primarily adult-onset conditions, often debilitating and fatal in absence of a cure, collectively pose a large burden on healthcare systems in an ageing world population. The pathological mechanisms driving disease onset are complex implicating several non-exclusive mechanisms of neuronal injury linked to RNA and protein toxic gain- and loss- of functions. Adding to the complexity of pathogenesis, microsatellite repeat expansions are polymorphic and found in coding as well as in non-coding regions of genes. They form secondary and tertiary structures involving G-quadruplexes and atypical helices in repeated GC-rich sequences. Unwinding of these structures by RNA helicases plays multiple roles in the expression of genes including repeat-associated non-AUG (RAN) translation of polymeric-repeat proteins with aggregating and cytotoxic properties. Here, we will briefly review the pathogenic mechanisms mediated by microsatellite repeat expansions prior to focus on the RNA helicases eIF4A, DDX3X and DHX36 which act as modifiers of RAN translation in C9ORF72-linked amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72-ALS/FTD) and Fragile X-associated tremor/ataxia syndrome (FXTAS). We will further review the RNA helicases DDX5/17, DHX9, Dicer and UPF1 which play additional roles in the dysregulation of RNA metabolism in repeat expansion disorders. In addition, we will contrast these with the roles of other RNA helicases such as DDX19/20, senataxin and others which have been associated with neurodegeneration independently of microsatellite repeat expansions. Finally, we will discuss the challenges and potential opportunities that are associated with the targeting of RNA helicases for the development of future therapeutic approaches.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133428PMC
http://dx.doi.org/10.3389/fgene.2022.886563DOI Listing

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