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REVIEW article
Front. Mol. Neurosci.
Sec. Brain Disease Mechanisms
Volume 17 - 2024 |
doi: 10.3389/fnmol.2024.1417961
Noches et al Epigenetics in ALS 1 Epigenetics in the formation of pathological aggregates in amyotrophic lateral sclerosis
Provisionally accepted- Western University, London, Canada
The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates.The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target.
Keywords: motor neuron, neurodegeneration, Liquid condensates, DNA Methylation, histone variants, chromodomain-helicase DNA-binding protein, RNA modifications
Received: 15 Apr 2024; Accepted: 23 Aug 2024.
Copyright: © 2024 Noches, Campos-Melo, Droppelmann and Strong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Michael J. Strong, Western University, London, Canada
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