Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutics in the Epigenomic Era

Overview

Journal Nat Rev Neurol

Specialty Neurology

Date 2015 Apr 22

PMID 25896087

Citations 105

Authors

Ximena Paez-Colasante

Claudia Figueroa-Romero

Stacey A Sakowski

Stephen A Goutman

Eva L Feldman

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li H . Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013; 110(47):E4530-9. PMC: 3839752. DOI: 10.1073/pnas.1318835110. View

Polymenidou M, Cleveland D . Prion-like spread of protein aggregates in neurodegeneration. J Exp Med. 2012; 209(5):889-93. PMC: 3348110. DOI: 10.1084/jem.20120741. View

Kawahara Y, Mieda-Sato A . TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc Natl Acad Sci U S A. 2012; 109(9):3347-52. PMC: 3295278. DOI: 10.1073/pnas.1112427109. View

Conradi S, Ronnevi L, Vesterberg O . Increased plasma levels of lead in patients with amyotrophic lateral sclerosis compared with control subjects as determined by flameless atomic absorption spectrophotometry. J Neurol Neurosurg Psychiatry. 1978; 41(5):389-93. PMC: 493043. DOI: 10.1136/jnnp.41.5.389. View

Janssen C, Schmalbach S, Boeselt S, Sarlette A, Dengler R, Petri S . Differential histone deacetylase mRNA expression patterns in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2010; 69(6):573-81. DOI: 10.1097/NEN.0b013e3181ddd404. View

Honda D, Ishigaki S, Iguchi Y, Fujioka Y, Udagawa T, Masuda A . The ALS/FTLD-related RNA-binding proteins TDP-43 and FUS have common downstream RNA targets in cortical neurons. FEBS Open Bio. 2013; 4:1-10. PMC: 3851184. DOI: 10.1016/j.fob.2013.11.001. View

Tremolizzo L, Messina P, Conti E, Sala G, Cecchi M, Airoldi L . Whole-blood global DNA methylation is increased in amyotrophic lateral sclerosis independently of age of onset. Amyotroph Lateral Scler Frontotemporal Degener. 2013; 15(1-2):98-105. DOI: 10.3109/21678421.2013.851247. View

King I, Yartseva V, Salas D, Kumar A, Heidersbach A, Ando D . The RNA-binding protein TDP-43 selectively disrupts microRNA-1/206 incorporation into the RNA-induced silencing complex. J Biol Chem. 2014; 289(20):14263-71. PMC: 4022891. DOI: 10.1074/jbc.M114.561902. View

Dewey C, Cenik B, Sephton C, Dries D, Mayer 3rd P, Good S . TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Mol Cell Biol. 2010; 31(5):1098-108. PMC: 3067820. DOI: 10.1128/MCB.01279-10. View

10.

Conradi S, Ronnevi L, Nise G, Vesterberg O . Abnormal distribution of lead in amyotrophic lateral sclerosis--reestimation of lead in the cerebrospinal fluid. J Neurol Sci. 1980; 48(3):413-8. DOI: 10.1016/0022-510x(80)90112-4. View

11.

Giagheddu M, Puggioni G, Masala C, Biancu F, Pirari G, Piras M . Epidemiologic study of amyotrophic lateral sclerosis in Sardinia, Italy. Acta Neurol Scand. 1983; 68(6):394-404. DOI: 10.1111/j.1600-0404.1983.tb04849.x. View

12.

DAmbrogio A, Buratti E, Stuani C, Guarnaccia C, Romano M, Ayala Y . Functional mapping of the interaction between TDP-43 and hnRNP A2 in vivo. Nucleic Acids Res. 2009; 37(12):4116-26. PMC: 2709582. DOI: 10.1093/nar/gkp342. View

13.

Lee Y, Kim M, Han J, Yeom K, Lee S, Baek S . MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004; 23(20):4051-60. PMC: 524334. DOI: 10.1038/sj.emboj.7600385. View

14.

Simpson C, Lemmens R, Miskiewicz K, Broom W, Hansen V, van Vught P . Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum Mol Genet. 2008; 18(3):472-81. PMC: 2638803. DOI: 10.1093/hmg/ddn375. View

15.

Niikura T, Kita Y, Abe Y . SUMO3 modification accelerates the aggregation of ALS-linked SOD1 mutants. PLoS One. 2014; 9(6):e101080. PMC: 4074151. DOI: 10.1371/journal.pone.0101080. View

16.

De Felice B, Annunziata A, Fiorentino G, Borra M, Biffali E, Coppola C . miR-338-3p is over-expressed in blood, CFS, serum and spinal cord from sporadic amyotrophic lateral sclerosis patients. Neurogenetics. 2014; 15(4):243-53. DOI: 10.1007/s10048-014-0420-2. View

17.

Tan L, Yu J, Tan L . Causes and Consequences of MicroRNA Dysregulation in Neurodegenerative Diseases. Mol Neurobiol. 2014; 51(3):1249-62. DOI: 10.1007/s12035-014-8803-9. View

18.

Hutvagner G, McLachlan J, Pasquinelli A, Balint E, Tuschl T, Zamore P . A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science. 2001; 293(5531):834-8. DOI: 10.1126/science.1062961. View

19.

Jobe E, McQuate A, Zhao X . Crosstalk among Epigenetic Pathways Regulates Neurogenesis. Front Neurosci. 2012; 6:59. PMC: 3347638. DOI: 10.3389/fnins.2012.00059. View

20.

de Jong S, Huisman M, Sutedja N, van der Kooi A, de Visser M, Schelhaas H . Smoking, alcohol consumption, and the risk of amyotrophic lateral sclerosis: a population-based study. Am J Epidemiol. 2012; 176(3):233-9. DOI: 10.1093/aje/kws015. View