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Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era

Nature Reviews Neurology volume 11, pages 266–279 (2015)Cite this article

Subjects

Key Points

  • The pathogenesis of amyotrophic lateral sclerosis (ALS) is mediated by genetic variation, environmental exposure and epigenetic regulation

  • Epigenetic mechanisms might explain how gene expression and function are controlled, and how gene–gene and gene–environmental interactions are mediated

  • DNA methylation, histone remodeling, RNA editing, and microRNA (miRNA) modifications are epigenetic mechanisms that are dysregulated in ALS models and in patients

  • miRNAs modulate many physiological processes through an intricate network of fine-tuning robustness and complexity of the transcriptome and proteome

  • miRNA pathway disruptions could be a cause or consequence of altered RNA and protein metabolism, the inflammatory response, cytotoxicity and/or neuromuscular junction impairments, all of which underlie ALS pathology

  • miRNAs have great potential as novel biomarkers and therapeutic targets for ALS and other neurodegenerative diseases

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor neurons, which results in weakness and atrophy of voluntary skeletal muscles. Treatments do not modify the disease trajectory effectively, and only modestly improve survival. A complex interaction between genes, environmental exposure and impaired molecular pathways contributes to pathology in patients with ALS. Epigenetic mechanisms control the hereditary and reversible regulation of gene expression without altering the basic genetic code. Aberrant epigenetic patterns—including abnormal microRNA (miRNA) biogenesis and function, DNA modifications, histone remodeling, and RNA editing—are acquired throughout life and are influenced by environmental factors. Thus, understanding the molecular processes that lead to epigenetic dysregulation in patients with ALS might facilitate the discovery of novel therapeutic targets and biomarkers that could reduce diagnostic delay. These achievements could prove crucial for successful disease modification in patients with ALS. We review the latest findings regarding the role of miRNA modifications and other epigenetic mechanisms in ALS, and discuss their potential as therapeutic targets.

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Figure 1: Disruption of miRNA biogenesis and function by cytoplasmic protein aggregates.
Figure 2: Dysregulation of miRNA biogenesis and function may be a cause and/or consequence of ALS pathogenesis.

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Acknowledgements

Funding support during the preparation of this Review was provided by the Program for Neurology Research & Discovery, the A. Alfred Taubman Medical Research Institute, the Agency for Toxic Substances and Disease Registry (contract # 200-2013-56,856 to E.L.F. and S.G.), and the National Institutes of Health (R01 NS077982 to E.L.F.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would also like to thank Dr Dana Carter for critically reviewing the manuscript.

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  1. Department of Neurology, University of Michigan, 1500 East Medical Centre Drive, 1914 Taubman Centre SPC 5316, Ann Arbor, 48109, MI, USA

    Ximena Paez-Colasante, Claudia Figueroa-Romero, Stephen A. Goutman & Eva L. Feldman

  2. The A. Alfred Taubman Medical Research Institute, University of Michigan, 109 Zina Pitcher Place, 5017 A. Alfred Taubman Biomedical Science Research Building, Ann Arbor, 48109, MI, USA

    Stacey A. Sakowski

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X.P.-C. and C.F.-R. researched data and wrote the article. X.P.-C., S.A.S. and E.L.F. made substantial contributions to the discussion of content. All authors reviewed and edited the manuscript before submission.

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Paez-Colasante, X., Figueroa-Romero, C., Sakowski, S. et al. Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era. Nat Rev Neurol 11, 266–279 (2015). https://doi.org/10.1038/nrneurol.2015.57

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