Thanks to visit codestin.com
Credit goes to link.springer.com

Skip to main content
Springer Nature Link
Log in

Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis

  • Review
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. Whole-genome sequencing has identified many novel ALS-associated genes, but genetics alone cannot fully explain the onset of ALS and an effective treatment is still lacking. Moreover, we need more biomarkers for accurate diagnosis and assessment of disease prognosis. Epigenetics, which includes DNA methylation and hydroxymethylation, histone modifications, chromatin remodeling, and non-coding RNAs, influences gene transcription and expression by affecting chromatin accessibility and transcription factor binding without altering genetic information. These processes play a role in the onset and progression of ALS. Epigenetic targets can serve as potential biomarkers and more importantly, the reversibility of epigenetic changes supports their potential role as versatile therapeutic targets in ALS. This review summarized the alterations in different epigenetic modulations in ALS. Additionally, given the close association between aberrant metabolic profiles characterized by hypoxia and high glycolytic metabolism in ALS and epigenetic changes, we also integrate epigenetics with metabolomics. Finally, we discuss the application of therapies based on epigenetic mechanisms in ALS. Our data integration helps to identify potential diagnostic and prognostic biomarkers and support the development of new effective therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from £29.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

Data availability

Not applicable.

Abbreviations

ALS:

Amyotrophic lateral sclerosis

ND:

Neurodegenerative disease

hPTM:

Histone post-translational modifications

ncRNA:

Non-coding RNA

TF:

Transcription factor

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

HD:

Huntington’s disease

DNMT:

DNA methyltransferase

5mC:

5-Methylcytosine

EWAS:

Epigenome-Wide Association Study

DMP:

Differentially methylated positions

DMR:

Differentially methylated regions

MZ:

Monozygotic

eQTL:

Expression quantitative locus

DNAm-age:

Epigenetic age

CNS:

Central nervous system

ROS:

Reactive oxygen species

LMN:

Lower motor neuron

PMS:

Polymethylation score

WBC:

White blood cell

SLC:

Solute carriers

5hmC:

5-Hydroxymethylcytosine

NGS:

Next-generation sequencing

DhMRs:

Differentially hydroxymethylated regions

mtDNA:

Mitochondrial DNA

OXPHOS:

Oxidative phosphorylation

D-loop:

Displacement loop

bp:

Base pair

DNMT3a:

DNA methyltransferase 3a

PTM:

Post-translational modifications

HAT:

Histone Acetyltransferase

HDAC:

Histone Deacetylase

CBP:

CREB-binding protein

ELP3:

Elongator subunit 3

Tip60:

Tat interactive protein 60 kDa

SG:

Stress granule

NAD + :

Nicotinamide adenine dinucleotide

NDST3:

N‐deacetylase and N‐sulfotransferase 3

PR:

Proline-arginine

miRNAs:

MicroRNAs

lncRNAs:

Long non-coding RNAs

BDNF:

Brain-derived neurotrophic factor

CTE:

Chronic traumatic encephalopathy

EVs:

Extracellular vesicles

MS:

Multiple sclerosis

UMNs:

Upper motor neurons

Nfl:

Neurofilament light chain

PCR:

Polymerase chain reaction

ER:

Endoplasmic reticulum

piRNAs:

Piwi-interacting RNAs

iPSCs:

Induced pluripotent stem cells

NBs:

Nuclear bodies

LLPS:

Liquid–liquid phase separation

NAMPT:

Nicotinamide phosphoribosyl transferase

NMNATs:

Nicotinic acid mononucleotide transferases

AMPK:

Activated protein kinase

CREB:

CAMP-response element binding protein

SCA7:

Spinocerebellar ataxia type 7

NR:

NAD + precursors

PT:

Polyphenols like resveratrol

ACLY:

ATP-citrate lyase

ACC1:

Acetyl-CoA carboxylase 1

SBMA:

Spinal and bulbar muscular atrophy

TLR4:

Toll-like receptor 4

ASO:

Antisense oligonucleotide

HDACi:

HDAC inhibitors

DNMTi:

DNMT inhibitors

sALS:

Sporadic ALS

fALS:

Familial ALS

References

  1. Therrien M, Dion PA, Rouleau GA (2016) ALS: recent developments from genetics studies. Curr Neurol Neurosci Rep 16:59. https://doi.org/10.1007/s11910-016-0658-1

    Article  CAS  PubMed  Google Scholar 

  2. Charcot JM (1869) Deux cas d'atrophie musculaire progressive avec lesions de la substance grice et des faisceaux anterolateraux de la moelle epiniere. 2, 354,629,744

  3. Rotunno MS, Bosco DA (2013) An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis. Front Cell Neurosci 7:253. https://doi.org/10.3389/fncel.2013.00253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Al-Chalabi A, Hardiman O (2013) The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol 9:617–628. https://doi.org/10.1038/nrneurol.2013.203

    Article  CAS  PubMed  Google Scholar 

  5. Ayers JI, Borchelt DR (2021) Phenotypic diversity in ALS and the role of poly-conformational protein misfolding. Acta Neuropathol 142:41–55. https://doi.org/10.1007/s00401-020-02222-x

    Article  PubMed  Google Scholar 

  6. Pang SY et al (2017) The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review. Transl Neurodegener 6:27. https://doi.org/10.1186/s40035-017-0098-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Renton AE, Chiò A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17:17–23. https://doi.org/10.1038/nn.3584

    Article  CAS  PubMed  Google Scholar 

  8. Piaceri I et al (2012) Clinical heterogeneity in Italian patients with amyotrophic lateral sclerosis. Clin Genet 82:83–87. https://doi.org/10.1111/j.1399-0004.2011.01726.x

    Article  CAS  PubMed  Google Scholar 

  9. Zhang M et al (2016) Genetic and epigenetic study of ALS-discordant identical twins with double mutations in SOD1 and ARHGEF28. J Neurol Neurosurg Psychiatry 87:1268–1270. https://doi.org/10.1136/jnnp-2016-313592

    Article  PubMed  Google Scholar 

  10. Tammen SA, Friso S, Choi SW (2013) Epigenetics: the link between nature and nurture. Mol Aspects Med 34:753–764. https://doi.org/10.1016/j.mam.2012.07.018

    Article  CAS  PubMed  Google Scholar 

  11. Yamaguchi M, Omori K, Asada S, Yoshida H (2021) Epigenetic regulation of ALS and CMT: a lesson from drosophila models. Int J Mol Sci. https://doi.org/10.3390/ijms22020491

    Article  PubMed  PubMed Central  Google Scholar 

  12. Varela MA, Roberts TC, Wood MJ (2013) Epigenetics and ncRNAs in brain function and disease: mechanisms and prospects for therapy. Neurother J Am Soc Exper NeuroTherap 10:621–631. https://doi.org/10.1007/s13311-013-0212-7

    Article  CAS  Google Scholar 

  13. Pal S, Tyler JK (2016) Epigenetics and aging. Sci Adv 2:e1600584. https://doi.org/10.1126/sciadv.1600584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Irwin KE, Sheth U, Wong PC, Gendron TF (2024) Fluid biomarkers for amyotrophic lateral sclerosis: a review. Mol Neurodegener 19:9. https://doi.org/10.1186/s13024-023-00685-6

    Article  PubMed  PubMed Central  Google Scholar 

  15. Vandoorne T, De Bock K, Van Den Bosch L (2018) Energy metabolism in ALS: An underappreciated opportunity? Acta Neuropathol 135:489–509. https://doi.org/10.1007/s00401-018-1835-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bouteloup C et al (2009) Hypermetabolism in ALS patients: an early and persistent phenomenon. J Neurol 256:1236–1242. https://doi.org/10.1007/s00415-009-5100-z

    Article  CAS  PubMed  Google Scholar 

  17. Henderson RD, Kepp KP, Eisen A (2022) ALS/FTD: evolution, aging, and cellular metabolic exhaustion. Front Neurol 13:890203. https://doi.org/10.3389/fneur.2022.890203

    Article  PubMed  PubMed Central  Google Scholar 

  18. Angeloni A, Bogdanovic O (2019) Enhancer DNA methylation: implications for gene regulation. Essays Biochem 63:707–715. https://doi.org/10.1042/ebc20190030

    Article  CAS  PubMed  Google Scholar 

  19. Antunes C, Sousa N, Pinto L, Marques CJ (2019) TET enzymes in neurophysiology and brain function. Neurosci Biobehav Rev 102:337–344. https://doi.org/10.1016/j.neubiorev.2019.05.006

    Article  CAS  PubMed  Google Scholar 

  20. Zhang M et al (2020) DNA methylation age acceleration is associated with ALS age of onset and survival. Acta Neuropathol 139:943–946. https://doi.org/10.1007/s00401-020-02131-z

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zhao Y et al (2024) Epigenetic age acceleration is associated with occupational exposures, sex, and survival in amyotrophic lateral sclerosis. EBioMedicine 109:105383. https://doi.org/10.1016/j.ebiom.2024.105383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nabais MF et al (2020) Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis. NPJ Genom Med 5:10. https://doi.org/10.1038/s41525-020-0118-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Appleby-Mallinder C et al (2021) TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol 47:61–72. https://doi.org/10.1111/nan.12625

    Article  CAS  PubMed  Google Scholar 

  24. Freydenzon A et al (2022) Association between DNA methylation variability and self-reported exposure to heavy metals. Sci Rep 12:10582. https://doi.org/10.1038/s41598-022-13892-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cai Z, Jia X, Liu M, Yang X, Cui L (2022) Epigenome-wide DNA methylation study of whole blood in patients with sporadic amyotrophic lateral sclerosis. Chin Med J 135:1466–1473. https://doi.org/10.1097/cm9.0000000000002090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ruf WP et al (2022) Methylome analysis of ALS patients and presymptomatic mutation carriers in blood cells. Neurobiol Aging 116:16–24. https://doi.org/10.1016/j.neurobiolaging.2022.04.003

    Article  CAS  PubMed  Google Scholar 

  27. Tazelaar GHP et al (2023) Whole genome sequencing analysis reveals post-zygotic mutation variability in monozygotic twins discordant for amyotrophic lateral sclerosis. Neurobiol Aging 122:76–87. https://doi.org/10.1016/j.neurobiolaging.2022.11.010

    Article  CAS  PubMed  Google Scholar 

  28. Yazar V et al (2023) DNA Methylation analysis in monozygotic twins discordant for ALS in blood cells. Epigenet Insights 16:25168657231172160. https://doi.org/10.1177/25168657231172159

    Article  PubMed  PubMed Central  Google Scholar 

  29. Hop PJ et al (2022) Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS. Sci Transl Med 14:eabj0264. https://doi.org/10.1126/scitranslmed.abj0264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kim BW, Jeong YE, Wong M, Martin LJ (2020) DNA damage accumulates and responses are engaged in human ALS brain and spinal motor neurons and DNA repair is activatable in iPSC-derived motor neurons with SOD1 mutations. Acta Neuropathol Commun 8:7. https://doi.org/10.1186/s40478-019-0874-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang T et al (2024) Genome-wide DNA methylation analysis related to ALS patient progression and survival. J Neurol. https://doi.org/10.1007/s00415-024-12222-6

    Article  PubMed  PubMed Central  Google Scholar 

  32. Esanov R et al (2016) C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells. Exp Neurol 277:171–177. https://doi.org/10.1016/j.expneurol.2015.12.022

    Article  CAS  PubMed  Google Scholar 

  33. Zhang M et al (2021) Combined epigenetic/genetic study identified an ALS age of onset modifier. Acta Neuropathol Commun 9:75. https://doi.org/10.1186/s40478-021-01183-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang M et al (2018) A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers. Brain J Neurol 141:2895–2907. https://doi.org/10.1093/brain/awy238

    Article  Google Scholar 

  35. Hu C, Tao L, Cao X, Chen L (2020) The solute carrier transporters and the brain: physiological and pharmacological implications. Asian J Pharm Sci 15:131–144. https://doi.org/10.1016/j.ajps.2019.09.002

    Article  PubMed  Google Scholar 

  36. Xie Y, Luo X, He H, Tang M (2021) Novel insight into the role of immune dysregulation in amyotrophic lateral sclerosis based on bioinformatic analysis. Front Neurosci 15:657465. https://doi.org/10.3389/fnins.2021.657465

    Article  PubMed  PubMed Central  Google Scholar 

  37. Koçoğlu C et al (2021) No association of CpG SNP rs9357140 with onset age in Belgian C9orf72 repeat expansion carriers. Neurobiol Aging 97(145):e141-145.e144. https://doi.org/10.1016/j.neurobiolaging.2020.07.021

    Article  CAS  Google Scholar 

  38. Zhang M et al (2017) DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients. Acta Neuropathol 134:271–279. https://doi.org/10.1007/s00401-017-1713-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li Y et al (2023) Globally reduced N(6)-methyladenosine (m(6)A) in C9ORF72-ALS/FTD dysregulates RNA metabolism and contributes to neurodegeneration. Nat Neurosci 26:1328–1338. https://doi.org/10.1038/s41593-023-01374-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Martin LJ, Adams DA, Niedzwiecki MV, Wong M (2022) Aberrant DNA and RNA methylation occur in spinal cord and skeletal muscle of human SOD1 mouse models of ALS and in human ALS: targeting DNA methylation is therapeutic. Cells. https://doi.org/10.3390/cells11213448

    Article  PubMed  PubMed Central  Google Scholar 

  41. Gomes C et al (2019) Cortical neurotoxic astrocytes with early ALS pathology and miR-146a deficit replicate gliosis markers of symptomatic SOD1G93A mouse model. Mol Neurobiol 56:2137–2158. https://doi.org/10.1007/s12035-018-1220-8

    Article  CAS  PubMed  Google Scholar 

  42. Xie M et al (2022) TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration. Nat Neurosci 25:26–38. https://doi.org/10.1038/s41593-021-00975-6

    Article  CAS  PubMed  Google Scholar 

  43. Figueroa-Romero C et al (2012) Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis. PLoS ONE 7:e52672. https://doi.org/10.1371/journal.pone.0052672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ozyurt T, Gautam M (2021) Differential epigenetic signature of corticospinal motor neurons in ALS. Brain Sci. https://doi.org/10.3390/brainsci11060754

    Article  PubMed  PubMed Central  Google Scholar 

  45. Esanov R et al (2017) A C9ORF72 BAC mouse model recapitulates key epigenetic perturbations of ALS/FTD. Mol Neurodegener 12:46. https://doi.org/10.1186/s13024-017-0185-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nikolac Perkovic M et al (2021) Epigenetics of Alzheimer’s disease. Biomolecules. https://doi.org/10.3390/biom11020195

    Article  PubMed  PubMed Central  Google Scholar 

  47. Coppedè F, Stoccoro A (2019) Mitoepigenetics and neurodegenerative diseases. Front Endocrinol 10:86. https://doi.org/10.3389/fendo.2019.00086

    Article  Google Scholar 

  48. Chen W et al (2022) The pathogenesis of amyotrophic lateral sclerosis: mitochondrial dysfunction, protein misfolding and epigenetics. Brain Res 1786:147904. https://doi.org/10.1016/j.brainres.2022.147904

    Article  CAS  PubMed  Google Scholar 

  49. Stoccoro A, Coppedè F (2021) Mitochondrial DNA Methylation and Human Diseases. Int J Mol Sci. https://doi.org/10.3390/ijms22094594

    Article  PubMed  PubMed Central  Google Scholar 

  50. Chestnut BA et al (2011) Epigenetic regulation of motor neuron cell death through DNA methylation. J Neurosci Off J Soc Neurosci 31:16619–16636. https://doi.org/10.1523/jneurosci.1639-11.2011

    Article  CAS  Google Scholar 

  51. Wong M, Gertz B, Chestnut BA, Martin LJ (2013) Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS. Front Cell Neurosci 7:279. https://doi.org/10.3389/fncel.2013.00279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Stoccoro A et al (2018) Mitochondrial DNA copy number and D-loop region methylation in carriers of amyotrophic lateral sclerosis gene mutations. Epigenomics 10:1431–1443. https://doi.org/10.2217/epi-2018-0072

    Article  CAS  PubMed  Google Scholar 

  53. Stoccoro A et al (2024) Mitochondrial D-loop methylation levels inversely correlate with disease duration in amyotrophic lateral sclerosis. Epigenomics 16:203–214. https://doi.org/10.2217/epi-2023-0265

    Article  CAS  PubMed  Google Scholar 

  54. Stoccoro A et al (2020) Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis. Clin Epigenetics 12:137. https://doi.org/10.1186/s13148-020-00933-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Jenuwein T, Allis CD (2001) Translating the histone code. Science (New York NY) 293:1074–1080. https://doi.org/10.1126/science.1063127

    Article  CAS  Google Scholar 

  56. Zhang M et al (2020) Histone variants and histone modifications in neurogenesis. Trends Cell Biol 30:869–880. https://doi.org/10.1016/j.tcb.2020.09.003

    Article  CAS  PubMed  Google Scholar 

  57. Zhang Y et al (2021) Overview of histone modification. Adv Exp Med Biol 1283:1–16. https://doi.org/10.1007/978-981-15-8104-5_1

    Article  CAS  PubMed  Google Scholar 

  58. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45. https://doi.org/10.1038/47412

    Article  CAS  PubMed  Google Scholar 

  59. Bennett SA, Tanaz R, Cobos SN, Torrente MP (2019) Epigenetics in amyotrophic lateral sclerosis: a role for histone post-translational modifications in neurodegenerative disease. Transl Res J Lab Clin Med 204:19–30. https://doi.org/10.1016/j.trsl.2018.10.002

    Article  CAS  Google Scholar 

  60. Rouaux C et al (2003) Critical loss of CBP/p300 histone acetylase activity by caspase-6 during neurodegeneration. EMBO J 22:6537–6549. https://doi.org/10.1093/emboj/cdg615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chung YH, Joo KM, Lee YJ, Kim MJ, Cha CI (2003) Reactive astrocytes express cAMP-response-element-binding protein (CREB) binding protein (CBP) in the central nervous system of transgenic mice expressing a human Cu/Zn superoxide dismutase mutation. Neurosci Lett 343:159–162. https://doi.org/10.1016/s0304-3940(03)00353-7

    Article  CAS  PubMed  Google Scholar 

  62. Bento-Abreu A et al (2018) Elongator subunit 3 (ELP3) modifies ALS through tRNA modification. Hum Mol Genet 27:1276–1289. https://doi.org/10.1093/hmg/ddy043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Beaver M et al (2020) Disruption of Tip60 HAT mediated neural histone acetylation homeostasis is an early common event in neurodegenerative diseases. Sci Rep 10:18265. https://doi.org/10.1038/s41598-020-75035-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sanna S et al (2020) HDAC1 inhibition ameliorates TDP-43-induced cell death in vitro and in vivo. Cell Death Dis 11:369. https://doi.org/10.1038/s41419-020-2580-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Janssen C et al (2010) Differential histone deacetylase mRNA expression patterns in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 69:573–581. https://doi.org/10.1097/NEN.0b013e3181ddd404

    Article  CAS  PubMed  Google Scholar 

  66. Pigna E et al (2019) Histone deacetylase 4 protects from denervation and skeletal muscle atrophy in a murine model of amyotrophic lateral sclerosis. EBioMedicine 40:717–732. https://doi.org/10.1016/j.ebiom.2019.01.038

    Article  PubMed  PubMed Central  Google Scholar 

  67. Valle C et al (2014) Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways. Cell Death Dis 5:e1296. https://doi.org/10.1038/cddis.2014.247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Miskiewicz K et al (2014) HDAC6 is a Bruchpilot deacetylase that facilitates neurotransmitter release. Cell Rep 8:94–102. https://doi.org/10.1016/j.celrep.2014.05.051

    Article  CAS  PubMed  Google Scholar 

  69. Chen S et al (2015) Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis. Neurosci Bull 31:459–468. https://doi.org/10.1007/s12264-015-1539-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kim D et al (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26:3169–3179. https://doi.org/10.1038/sj.emboj.7601758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Körner S et al (2013) Differential sirtuin expression patterns in amyotrophic lateral sclerosis (ALS) postmortem tissue: neuroprotective or neurotoxic properties of sirtuins in ALS? Neurodegener Dis 11:141–152. https://doi.org/10.1159/000338048

    Article  CAS  PubMed  Google Scholar 

  72. Harlan BA et al (2020) Evaluation of the NAD(+) biosynthetic pathway in ALS patients and effect of modulating NAD(+) levels in hSOD1-linked ALS mouse models. Exp Neurol 327:113219. https://doi.org/10.1016/j.expneurol.2020.113219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Buck E et al (2017) Comparison of Sirtuin 3 Levels in ALS and Huntington’s disease-differential effects in human tissue samples vs. transgenic mouse models. Front Mol Neurosci 10:156. https://doi.org/10.3389/fnmol.2017.00156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Rossaert E et al (2019) Restoration of histone acetylation ameliorates disease and metabolic abnormalities in a FUS mouse model. Acta Neuropathol Commun 7:107. https://doi.org/10.1186/s40478-019-0750-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Belzil VV et al (2013) Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol 126:895–905. https://doi.org/10.1007/s00401-013-1199-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jury N et al (2020) Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice. Clin Epigenet 12:32. https://doi.org/10.1186/s13148-020-0816-9

    Article  CAS  Google Scholar 

  77. Marzullo M et al (2023) Su(var)3–9 mediates age-dependent increase in H3K9 methylation on TDP-43 promoter triggering neurodegeneration. Cell Death Discov 9:357. https://doi.org/10.1038/s41420-023-01643-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhang YJ et al (2019) Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. Science (New York NY). https://doi.org/10.1126/science.aav2606

    Article  PubMed Central  Google Scholar 

  79. Masala A et al (2018) Epigenetic changes associated with the expression of amyotrophic lateral sclerosis (ALS) causing genes. Neuroscience 390:1–11. https://doi.org/10.1016/j.neuroscience.2018.08.009

    Article  CAS  PubMed  Google Scholar 

  80. Tibshirani M et al (2015) Cytoplasmic sequestration of FUS/TLS associated with ALS alters histone marks through loss of nuclear protein arginine methyltransferase 1. Hum Mol Genet 24:773–786. https://doi.org/10.1093/hmg/ddu494

    Article  CAS  PubMed  Google Scholar 

  81. Bruneteau G et al (2013) Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression. Brain J Neurol 136:2359–2368. https://doi.org/10.1093/brain/awt164

    Article  Google Scholar 

  82. Renzini A et al (2022) Sex and HDAC4 differently affect the pathophysiology of amyotrophic lateral sclerosis in SOD1-G93A mice. Int J Mol Sci. https://doi.org/10.3390/ijms24010098

    Article  PubMed  PubMed Central  Google Scholar 

  83. Lazo-Gómez R, Ramírez-Jarquín UN, Tovar YRLB, Tapia R (2013) Histone deacetylases and their role in motor neuron degeneration. Front Cell Neurosci 7:243. https://doi.org/10.3389/fncel.2013.00243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lee JY et al (2010) HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J 29:969–980. https://doi.org/10.1038/emboj.2009.405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Pandey UB et al (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447:859–863. https://doi.org/10.1038/nature05853

    Article  CAS  PubMed  Google Scholar 

  86. Cohen TJ et al (2015) An acetylation switch controls TDP-43 function and aggregation propensity. Nat Commun 6:5845. https://doi.org/10.1038/ncomms6845

    Article  CAS  PubMed  Google Scholar 

  87. Chen Y, Cohen TJ (2019) Aggregation of the nucleic acid-binding protein TDP-43 occurs via distinct routes that are coordinated with stress granule formation. J Biol Chem 294:3696–3706. https://doi.org/10.1074/jbc.RA118.006351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gal J et al (2013) HDAC6 regulates mutant SOD1 aggregation through two SMIR motifs and tubulin acetylation. J Biol Chem 288:15035–15045. https://doi.org/10.1074/jbc.M112.431957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Watanabe S et al (2020) Aggresome formation and liquid-liquid phase separation independently induce cytoplasmic aggregation of TAR DNA-binding protein 43. Cell Death Dis 11:909. https://doi.org/10.1038/s41419-020-03116-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Del Rosso G et al (2021) HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS. Front Cell Dev Biol 9:809942. https://doi.org/10.3389/fcell.2021.809942

    Article  PubMed  Google Scholar 

  91. Kim SH, Shanware NP, Bowler MJ, Tibbetts RS (2010) Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA. J Biol Chem 285:34097–34105. https://doi.org/10.1074/jbc.M110.154831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Taes I et al (2013) Hdac6 deletion delays disease progression in the SOD1G93A mouse model of ALS. Hum Mol Genet 22:1783–1790. https://doi.org/10.1093/hmg/ddt028

    Article  CAS  PubMed  Google Scholar 

  93. Lee JC et al (2012) Region-specific changes in the immunoreactivity of SIRT1 expression in the central nervous system of SOD1(G93A) transgenic mice as an in vivo model of amyotrophic lateral sclerosis. Brain Res 1433:20–28. https://doi.org/10.1016/j.brainres.2011.11.019

    Article  CAS  PubMed  Google Scholar 

  94. Wang J, Zhang Y, Tang L, Zhang N, Fan D (2011) Protective effects of resveratrol through the up-regulation of SIRT1 expression in the mutant hSOD1-G93A-bearing motor neuron-like cell culture model of amyotrophic lateral sclerosis. Neurosci Lett 503:250–255. https://doi.org/10.1016/j.neulet.2011.08.047

    Article  CAS  PubMed  Google Scholar 

  95. Hor JH et al (2021) ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation. Cell Death Differ 28:1379–1397. https://doi.org/10.1038/s41418-020-00664-0

    Article  CAS  PubMed  Google Scholar 

  96. Tang Q et al (2021) NDST3 deacetylates α-tubulin and suppresses V-ATPase assembly and lysosomal acidification. EMBO J 40:e107204. https://doi.org/10.15252/embj.2020107204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Gong F, Miller KM (2019) Histone methylation and the DNA damage response. Mutat Res, Rev Mutat Res 780:37–47. https://doi.org/10.1016/j.mrrev.2017.09.003

    Article  CAS  PubMed  Google Scholar 

  98. Recillas-Targa F (2022) Cancer epigenetics: an overview. Arch Med Res 53:732–740. https://doi.org/10.1016/j.arcmed.2022.11.003

    Article  CAS  PubMed  Google Scholar 

  99. Tibshirani M et al (2017) Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis. Hum Mol Genet 26:4142–4152. https://doi.org/10.1093/hmg/ddx301

    Article  CAS  PubMed  Google Scholar 

  100. Li W et al (2022) Nuclear RIPK1 promotes chromatin remodeling to mediate inflammatory response. Cell Res 32:621–637. https://doi.org/10.1038/s41422-022-00673-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wei J et al (2023) Elevated peripheral levels of receptor-interacting protein kinase 1 (RIPK1) and IL-8 as biomarkers of human amyotrophic lateral sclerosis. Signal Transduct Target Ther 8:451. https://doi.org/10.1038/s41392-023-01713-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jakubowski JL, Labrie V (2017) Epigenetic biomarkers for Parkinson’s disease: from diagnostics to therapeutics. J Parkinsons Dis 7:1–12. https://doi.org/10.3233/jpd-160914

    Article  PubMed  PubMed Central  Google Scholar 

  103. Si Y et al (2018) Muscle microRNA signatures as biomarkers of disease progression in amyotrophic lateral sclerosis. Neurobiol Dis 114:85–94. https://doi.org/10.1016/j.nbd.2018.02.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Banack SA, Dunlop RA, Cox PA (2020) An miRNA fingerprint using neural-enriched extracellular vesicles from blood plasma: towards a biomarker for amyotrophic lateral sclerosis/motor neuron disease. Open Biol 10:200116. https://doi.org/10.1098/rsob.200116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Banack SA, Dunlop RA, Stommel EW, Mehta P, Cox PA (2022) miRNA extracted from extracellular vesicles is a robust biomarker of amyotrophic lateral sclerosis. J Neurol Sci 442:120396. https://doi.org/10.1016/j.jns.2022.120396

    Article  CAS  PubMed  Google Scholar 

  106. De Felice B et al (2018) Wide-ranging analysis of MicroRNA profiles in sporadic amyotrophic lateral sclerosis using next-generation sequencing. Front Genet 9:310. https://doi.org/10.3389/fgene.2018.00310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Alvia M et al (2022) MicroRNA alterations in chronic traumatic encephalopathy and amyotrophic lateral sclerosis. Front Neurosci 16:855096. https://doi.org/10.3389/fnins.2022.855096

    Article  PubMed  PubMed Central  Google Scholar 

  108. Liu Y et al (2023) MicroRNA-23a-3p is upregulated in plasma exosomes of Bulbar-onset ALS patients and targets ERBB4. Neuroscience 524:65–78. https://doi.org/10.1016/j.neuroscience.2023.05.030

    Article  CAS  PubMed  Google Scholar 

  109. Russell AP et al (2013) Disruption of skeletal muscle mitochondrial network genes and miRNAs in amyotrophic lateral sclerosis. Neurobiol Dis 49:107–117. https://doi.org/10.1016/j.nbd.2012.08.015

    Article  CAS  PubMed  Google Scholar 

  110. Kmetzsch V et al (2022) MicroRNA signatures in genetic frontotemporal dementia and amyotrophic lateral sclerosis. Ann Clin Transl Neurol 9:1778–1791. https://doi.org/10.1002/acn3.51674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Cheng YF et al (2023) Signature of miRNAs derived from the circulating exosomes of patients with amyotrophic lateral sclerosis. Front Aging Neurosci 15:1106497. https://doi.org/10.3389/fnagi.2023.1106497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kmetzsch V et al (2021) Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 92:485–493. https://doi.org/10.1136/jnnp-2020-324647

    Article  PubMed  Google Scholar 

  113. Yelick J et al (2020) Elevated exosomal secretion of miR-124-3p from spinal neurons positively associates with disease severity in ALS. Exp Neurol 333:113414. https://doi.org/10.1016/j.expneurol.2020.113414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Liu H et al (2023) Systematic review and meta-analysis on microRNAs in amyotrophic lateral sclerosis. Brain Res Bull 194:82–89. https://doi.org/10.1016/j.brainresbull.2023.01.005

    Article  CAS  PubMed  Google Scholar 

  115. Ruffo P, Catalano S, La Bella V, Conforti FL (2023) Deregulation of plasma microRNA expression in a TARDBP-ALS family. Biomolecules. https://doi.org/10.3390/biom13040706

    Article  PubMed  PubMed Central  Google Scholar 

  116. Kurita H et al (2020) MicroRNA-5572 Is a novel MicroRNA-regulating SLC30A3 in sporadic amyotrophic lateral sclerosis. Int J Mol Sci. https://doi.org/10.3390/ijms21124482

    Article  PubMed  PubMed Central  Google Scholar 

  117. Abdelhamid RF et al (2022) piRNA/piwi protein complex as a potential biomarker in sporadic amyotrophic lateral sclerosis. Mol Neurobiol 59:1693–1705. https://doi.org/10.1007/s12035-021-02686-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Soliman R et al (2021) Assessment of diagnostic potential of some circulating microRNAs in amyotrophic lateral sclerosis patients, an Egyptian study. Clin Neurol Neurosurg 208:106883. https://doi.org/10.1016/j.clineuro.2021.106883

    Article  PubMed  Google Scholar 

  119. Giagnorio E et al (2023) MiR-146a in ALS: contribution to early peripheral nerve degeneration and relevance as disease biomarker. Int J Mol Sci. https://doi.org/10.3390/ijms24054610

    Article  PubMed  PubMed Central  Google Scholar 

  120. Dobrowolny G et al (2021) A longitudinal study defined circulating microRNAs as reliable biomarkers for disease prognosis and progression in ALS human patients. Cell death discovery 7:4. https://doi.org/10.1038/s41420-020-00397-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kim JA et al (2023) Small RNA sequencing of circulating small extracellular vesicles microRNAs in patients with amyotrophic lateral sclerosis. Sci Rep 13:5528. https://doi.org/10.1038/s41598-023-32717-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gomes BC et al (2023) Differential expression of miRNAs in amyotrophic lateral sclerosis patients. Mol Neurobiol 60:7104–7117. https://doi.org/10.1007/s12035-023-03520-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Freischmidt A et al (2014) Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers. Brain J Neurol 137:2938–2950. https://doi.org/10.1093/brain/awu249

    Article  Google Scholar 

  124. Panio A, Cava C, D’Antona S, Bertoli G, Porro D (2022) Diagnostic circulating miRNAs in sporadic amyotrophic lateral sclerosis. Front Med 9:861960. https://doi.org/10.3389/fmed.2022.861960

    Article  CAS  Google Scholar 

  125. Waller R et al (2017) Small RNA sequencing of sporadic amyotrophic lateral sclerosis cerebrospinal fluid reveals differentially expressed mirnas related to neural and glial activity. Front Neurosci 11:731. https://doi.org/10.3389/fnins.2017.00731

    Article  PubMed  Google Scholar 

  126. Rizzuti M et al (2018) MicroRNA expression analysis identifies a subset of downregulated miRNAs in ALS motor neuron progenitors. Sci Rep 8:10105. https://doi.org/10.1038/s41598-018-28366-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kaneko M et al (2015) Zinc transporters ZnT3 and ZnT6 are downregulated in the spinal cords of patients with sporadic amyotrophic lateral sclerosis. J Neurosci Res 93:370–379. https://doi.org/10.1002/jnr.23491

    Article  CAS  PubMed  Google Scholar 

  128. Kurita H, Okuda R, Yokoo K, Inden M, Hozumi I (2016) Protective roles of SLC30A3 against endoplasmic reticulum stress via ERK1/2 activation. Biochem Biophys Res Commun 479:853–859. https://doi.org/10.1016/j.bbrc.2016.09.119

    Article  CAS  PubMed  Google Scholar 

  129. Williams AH et al (2009) MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science (New York NY) 326:1549–1554. https://doi.org/10.1126/science.1181046

    Article  CAS  Google Scholar 

  130. Wakisaka KT et al (2019) Novel roles of Drosophila FUS and Aub responsible for piRNA biogenesis in neuronal disorders. Brain Res 1708:207–219. https://doi.org/10.1016/j.brainres.2018.12.028

    Article  CAS  PubMed  Google Scholar 

  131. Chen KW, Chen JA (2020) Functional roles of long non-coding RNAs in motor neuron development and disease. J Biomed Sci 27:38. https://doi.org/10.1186/s12929-020-00628-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Yu Y et al (2022) The expression discrepancy and characteristics of long non-coding RNAs in peripheral blood leukocytes from amyotrophic lateral sclerosis patients. Mol Neurobiol 59:3678–3689. https://doi.org/10.1007/s12035-022-02789-4

    Article  CAS  PubMed  Google Scholar 

  133. Provasek VE et al (2023) lncRNA sequencing reveals neurodegeneration-associated FUS mutations alter transcriptional landscape of iPS cells that persists in motor neurons. Cells. https://doi.org/10.3390/cells12202461

    Article  PubMed  PubMed Central  Google Scholar 

  134. Wang C et al (2020) Stress induces dynamic, cytotoxicity-antagonizing TDP-43 nuclear bodies via paraspeckle LncRNA NEAT1-mediated liquid-liquid phase separation. Mol Cell 79:443-458.e447. https://doi.org/10.1016/j.molcel.2020.06.019

    Article  CAS  PubMed  Google Scholar 

  135. An H et al (2019) ALS-linked FUS mutations confer loss and gain of function in the nucleus by promoting excessive formation of dysfunctional paraspeckles. Acta Neuropathol Commun 7:7. https://doi.org/10.1186/s40478-019-0658-x

    Article  PubMed  PubMed Central  Google Scholar 

  136. Suzuki H, Shibagaki Y, Hattori S, Matsuoka M (2019) C9-ALS/FTD-linked proline-arginine dipeptide repeat protein associates with paraspeckle components and increases paraspeckle formation. Cell Death Dis 10:746. https://doi.org/10.1038/s41419-019-1983-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Bajc Česnik A et al (2019) Nuclear RNA foci from C9ORF72 expansion mutation form paraspeckle-like bodies. J Cell Sci. https://doi.org/10.1242/jcs.224303

    Article  PubMed  Google Scholar 

  138. Swinnen B et al (2018) A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism. Acta Neuropathol 135:427–443. https://doi.org/10.1007/s00401-017-1796-5

    Article  CAS  PubMed  Google Scholar 

  139. Mori K et al (2016) Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide-repeat protein deposition. EMBO Rep 17:1314–1325. https://doi.org/10.15252/embr.201541724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Li PP et al (2016) ATXN2-AS, a gene antisense to ATXN2, is associated with spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis. Ann Neurol 80:600–615. https://doi.org/10.1002/ana.24761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Nishimoto Y, Nakagawa S, Okano H (2021) NEAT1 lncRNA and amyotrophic lateral sclerosis. Neurochem Int 150:105175. https://doi.org/10.1016/j.neuint.2021.105175

    Article  CAS  PubMed  Google Scholar 

  142. Grunseich C et al (2018) Senataxin mutation reveals how R-loops promote transcription by blocking DNA methylation at gene promoters. Mol Cell 69:426-437.e427. https://doi.org/10.1016/j.molcel.2017.12.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Bayona-Feliu A, Barroso S, Muñoz S, Aguilera A (2021) The SWI/SNF chromatin remodeling complex helps resolve R-loop-mediated transcription-replication conflicts. Nat Genet 53:1050–1063. https://doi.org/10.1038/s41588-021-00867-2

    Article  CAS  PubMed  Google Scholar 

  144. Cuartas J, Gangwani L (2022) R-loop mediated DNA damage and impaired DNA repair in spinal muscular atrophy. Front Cell Neurosci 16:826608. https://doi.org/10.3389/fncel.2022.826608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Mead RJ, Shan N, Reiser HJ, Marshall F, Shaw PJ (2023) Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discovery 22:185–212. https://doi.org/10.1038/s41573-022-00612-2

    Article  CAS  PubMed  Google Scholar 

  146. Giannini M et al (2020) TDP-43 mutations link amyotrophic lateral sclerosis with R-loop homeostasis and R loop-mediated DNA damage. PLoS Genet 16:e1009260. https://doi.org/10.1371/journal.pgen.1009260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Walker C, El-Khamisy SF (2018) Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia. Brain J Neurol 141:1247–1262. https://doi.org/10.1093/brain/awy076

    Article  Google Scholar 

  148. Tsui A, Kouznetsova VL, Kesari S, Fiala M, Tsigelny IF (2023) Role of senataxin in amyotrophic lateral sclerosis. J Mol Neurosci MN 73:996–1009. https://doi.org/10.1007/s12031-023-02169-0

    Article  CAS  PubMed  Google Scholar 

  149. Navia-Pelaez JM et al (2021) Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain. J Exper Med. https://doi.org/10.1084/jem.20202059

    Article  Google Scholar 

  150. Yang B et al (2023) NRF2 activation suppresses motor neuron ferroptosis induced by the SOD1(G93A) mutation and exerts neuroprotection in amyotrophic lateral sclerosis. Neurobiol Dis 184:106210. https://doi.org/10.1016/j.nbd.2023.106210

    Article  CAS  PubMed  Google Scholar 

  151. Kumar S, Lombard DB (2018) Functions of the sirtuin deacylase SIRT5 in normal physiology and pathobiology. Crit Rev Biochem Mol Biol 53:311–334. https://doi.org/10.1080/10409238.2018.1458071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Burg T, Rossaert E, Moisse M, Van Damme P, Van Den Bosch L (2021) Histone deacetylase inhibition regulates lipid homeostasis in a mouse model of amyotrophic lateral sclerosis. Int J Mol Sci. https://doi.org/10.3390/ijms222011224

    Article  PubMed  PubMed Central  Google Scholar 

  153. Liu Y, Wang J (2019) C9orf72-dependent lysosomal functions regulate epigenetic control of autophagy and lipid metabolism. Autophagy 15:913–914. https://doi.org/10.1080/15548627.2019.1580106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Liu Y et al (2018) A C9orf72-CARM1 axis regulates lipid metabolism under glucose starvation-induced nutrient stress. Genes Dev 32:1380–1397. https://doi.org/10.1101/gad.315564.118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Ferdinandusse S et al (2015) Clinical and biochemical characterization of four patients with mutations in ECHS1. Orphanet J Rare Dis 10:79. https://doi.org/10.1186/s13023-015-0290-1

    Article  PubMed  PubMed Central  Google Scholar 

  156. Zeng X et al (2017) Inhibition of miR-143 during ischemia cerebral injury protects neurones through recovery of the hexokinase 2-mediated glucose uptake. Biosci Rep. https://doi.org/10.1042/bsr20170216

  157. Suchy J, Lee S, Ahmed A, Shea TB (2010) Dietary supplementation with S-adenosyl methionine delays the onset of motor neuron pathology in a murine model of amyotrophic lateral sclerosis. NeuroMol Med 12:86–97. https://doi.org/10.1007/s12017-009-8089-7

    Article  CAS  Google Scholar 

  158. Ge T et al (2022) Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities. Cancer Commun (London, England) 42:1049–1082. https://doi.org/10.1002/cac2.12374

    Article  Google Scholar 

  159. Hernan-Godoy M, Rouaux C (2024) From environment to gene expression: epigenetic methylations and one-carbon metabolism in amyotrophic lateral sclerosis. Cells. https://doi.org/10.3390/cells13110967

    Article  PubMed  PubMed Central  Google Scholar 

  160. Zwilling M, Theiss C, Matschke V (2020) Caffeine and NAD(+) improve motor neural integrity of dissociated wobbler cells in vitro. Antiox Basel Switzerland. https://doi.org/10.3390/antiox9060460

    Article  Google Scholar 

  161. Harlan BA, Pehar M, Killoy KM, Vargas MR (2019) Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing ALS-linked mutant SOD1. FASEB J Off Publ Feder Am Soc Exper Biol 33:7084–7091. https://doi.org/10.1096/fj.201802752R

    Article  CAS  Google Scholar 

  162. Fels JA et al (2022) Gene expression profiles in sporadic ALS fibroblasts define disease subtypes and the metabolic effects of the investigational drug EH301. Hum Mol Genet 31:3458–3477. https://doi.org/10.1093/hmg/ddac118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Obrador E et al (2021) Nicotinamide riboside and pterostilbene cooperatively delay motor neuron failure in ALS SOD1(G93A) mice. Mol Neurobiol 58:1345–1371. https://doi.org/10.1007/s12035-020-02188-7

    Article  CAS  PubMed  Google Scholar 

  164. Xu S et al (2021) Role of mitochondria in neurodegenerative diseases: from an epigenetic perspective. Front Cell Dev Biol 9:688789. https://doi.org/10.3389/fcell.2021.688789

    Article  PubMed  PubMed Central  Google Scholar 

  165. Szelechowski M et al (2018) Metabolic reprogramming in amyotrophic lateral sclerosis. Sci Rep 8:3953. https://doi.org/10.1038/s41598-018-22318-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Lynch K (2023) Optimizing pharmacologic treatment for ALS to improve outcomes and quality of life. Am J Manag Care 29:S112-s119. https://doi.org/10.37765/ajmc.2023.89389

    Article  PubMed  Google Scholar 

  167. Wu C, Feng Y (2023) Exploring the potential of mindfulness-based therapy in the prevention and treatment of neurodegenerative diseases based on molecular mechanism studies. Front Neurosci 17:1097067. https://doi.org/10.3389/fnins.2023.1097067

    Article  PubMed  PubMed Central  Google Scholar 

  168. Ramic M et al (2021) Epigenetic small molecules rescue nucleocytoplasmic transport and DNA damage phenotypes in C9ORF72 ALS/FTD. Brain Sci. https://doi.org/10.3390/brainsci11111543

    Article  PubMed  PubMed Central  Google Scholar 

  169. Wang P et al (2020) Research progress of epigenetics in pathogenesis and treatment of malignant tumors. Zhongguo fei ai za zhi = Chin J Lung Cancer 23:91–100. https://doi.org/10.3779/j.issn.1009-3419.2020.02.04

    Article  Google Scholar 

  170. Lapucci A et al (2017) Effect of class II HDAC inhibition on glutamate transporter expression and survival in SOD1-ALS mice. Neurosci Lett 656:120–125. https://doi.org/10.1016/j.neulet.2017.07.033

    Article  CAS  PubMed  Google Scholar 

  171. Buonvicino D et al (2018) Effects of class II-selective histone deacetylase inhibitor on neuromuscular function and disease progression in SOD1-ALS mice. Neuroscience 379:228–238. https://doi.org/10.1016/j.neuroscience.2018.03.022

    Article  CAS  PubMed  Google Scholar 

  172. Guo W et al (2017) HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients. Nat Commun 8:861. https://doi.org/10.1038/s41467-017-00911-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Stoklund Dittlau K et al (2021) Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition. Stem Cell Reports 16:2213–2227. https://doi.org/10.1016/j.stemcr.2021.03.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Fazal R et al (2021) HDAC6 inhibition restores TDP-43 pathology and axonal transport defects in human motor neurons with TARDBP mutations. EMBO J 40:e106177. https://doi.org/10.15252/embj.2020106177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Liu ML et al (2024) Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease. Cell Death Dis 15:4. https://doi.org/10.1038/s41419-023-06395-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Wang WY et al (2013) Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat Neurosci 16:1383–1391. https://doi.org/10.1038/nn.3514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Patnaik D et al (2021) Exifone is a potent HDAC1 activator with neuroprotective activity in human neuronal models of neurodegeneration. ACS Chem Neurosci 12:271–284. https://doi.org/10.1021/acschemneuro.0c00308

    Article  CAS  PubMed  Google Scholar 

  178. Yun YC, Jeong SG, Kim SH, Cho GW (2019) Reduced sirtuin 1/adenosine monophosphate-activated protein kinase in amyotrophic lateral sclerosis patient-derived mesenchymal stem cells can be restored by resveratrol. J Tissue Eng Regen Med 13:110–115. https://doi.org/10.1002/term.2776

    Article  CAS  PubMed  Google Scholar 

  179. Bankole O et al (2022) Beneficial and sexually dimorphic response to combined HDAC inhibitor valproate and AMPK/SIRT1 pathway activator resveratrol in the treatment of ALS mice. Int J Mol Sci. https://doi.org/10.3390/ijms23031047

    Article  PubMed  PubMed Central  Google Scholar 

  180. Del Signore SJ et al (2009) Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice. Amyotroph Lateral Sclerosis Offic Publ World Feder Neurol Res Group Motor Neur Dis 10:85–94. https://doi.org/10.1080/17482960802226148

    Article  CAS  Google Scholar 

  181. Oh YS, Kim SH, Cho GW (2016) Functional restoration of amyotrophic lateral sclerosis patient-derived mesenchymal stromal cells through inhibition of DNA methyltransferase. Cell Mol Neurobiol 36:613–620. https://doi.org/10.1007/s10571-015-0242-2

    Article  CAS  PubMed  Google Scholar 

  182. Martinez B, Peplow PV (2022) MicroRNA expression in animal models of amyotrophic lateral sclerosis and potential therapeutic approaches. Neural Regen Res 17:728–740. https://doi.org/10.4103/1673-5374.322431

    Article  CAS  PubMed  Google Scholar 

  183. Provenzano F et al (2022) Micro-RNAs shuttled by extracellular vesicles secreted from mesenchymal stem cells dampen astrocyte pathological activation and support neuroprotection in in-vitro models of ALS. Cells. https://doi.org/10.3390/cells11233923

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  185. Mueller C et al (2020) SOD1 Suppression with adeno-associated virus and MicroRNA in familial ALS. N Engl J Med 383:151–158. https://doi.org/10.1056/NEJMoa2005056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Bennett CF (2019) Therapeutic antisense oligonucleotides are coming of age. Annu Rev Med 70:307–321. https://doi.org/10.1146/annurev-med-041217-010829

    Article  CAS  PubMed  Google Scholar 

  187. Van Daele SH, Masrori P, Van Damme P, Van Den Bosch L (2024) The sense of antisense therapies in ALS. Trends Mol Med. https://doi.org/10.1016/j.molmed.2023.12.003

    Article  PubMed  Google Scholar 

  188. Korobeynikov VA, Lyashchenko AK, Blanco-Redondo B, Jafar-Nejad P, Shneider NA (2022) Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat Med 28:104–116. https://doi.org/10.1038/s41591-021-01615-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Cabrera GT et al (2023) Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo. Gene Ther. https://doi.org/10.1038/s41434-023-00418-w

    Article  PubMed  Google Scholar 

  190. Liu Y et al (2022) Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD. Mol Therapy Nucl Acids 28:558–570. https://doi.org/10.1016/j.omtn.2022.04.007

    Article  CAS  Google Scholar 

  191. Tran H et al (2022) Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide. Nat Med 28:117–124. https://doi.org/10.1038/s41591-021-01557-6

    Article  CAS  PubMed  Google Scholar 

  192. Matsukawa K et al (2021) Long non-coding RNA NEAT1_1 ameliorates TDP-43 toxicity in in vivo models of TDP-43 proteinopathy. RNA Biol 18:1546–1554. https://doi.org/10.1080/15476286.2020.1860580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Vojta A et al (2016) Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acids Res 44:5615–5628. https://doi.org/10.1093/nar/gkw159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Cali CP, Park DS, Lee EB (2019) Targeted DNA methylation of neurodegenerative disease genes via homology directed repair. Nucleic Acids Res 47:11609–11622. https://doi.org/10.1093/nar/gkz979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Ababneh NA et al (2020) Correction of amyotrophic lateral sclerosis related phenotypes in induced pluripotent stem cell-derived motor neurons carrying a hexanucleotide expansion mutation in C9orf72 by CRISPR/Cas9 genome editing using homology-directed repair. Hum Mol Genet 29:2200–2217. https://doi.org/10.1093/hmg/ddaa106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Nuñez JK et al (2021) Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing. Cell 184:2503-2519.e2517. https://doi.org/10.1016/j.cell.2021.03.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Xiong X et al (2023) Epigenomic dissection of Alzheimer’s disease pinpoints causal variants and reveals epigenome erosion. Cell 186:4422-4437.e4421. https://doi.org/10.1016/j.cell.2023.08.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Zhang D et al (2023) Targeting epigenetic modifications in Parkinson’s disease therapy. Med Res Rev 43:1748–1777. https://doi.org/10.1002/med.21962

    Article  CAS  PubMed  Google Scholar 

  199. Nabais MF et al (2021) Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders. Genome Biol 22:90. https://doi.org/10.1186/s13059-021-02275-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Wu X et al (2008) Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol 11:1123–1134. https://doi.org/10.1017/s1461145708009024

    Article  CAS  PubMed  Google Scholar 

  201. Christoforidou E, Joilin G, Hafezparast M (2020) Potential of activated microglia as a source of dysregulated extracellular microRNAs contributing to neurodegeneration in amyotrophic lateral sclerosis. J Neuroinflammation 17:135. https://doi.org/10.1186/s12974-020-01822-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Malacarne C et al (2021) Dysregulation of muscle-specific micrornas as common pathogenic feature associated with muscle atrophy in ALS, SMA and SBMA: evidence from animal models and human patients. Int J Mol Sci. https://doi.org/10.3390/ijms22115673

    Article  PubMed  PubMed Central  Google Scholar 

  203. Montesinos P et al (2022) Ivosidenib and Azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med 386:1519–1531. https://doi.org/10.1056/NEJMoa2117344

    Article  CAS  PubMed  Google Scholar 

  204. Traxler L et al (2022) Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease. Cell Metab 34:1248-1263.e1246. https://doi.org/10.1016/j.cmet.2022.07.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Mohassel P et al (2021) Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. Nat Med 27:1197–1204. https://doi.org/10.1038/s41591-021-01346-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Hruska-Plochan M et al (2024) A model of human neural networks reveals NPTX2 pathology in ALS and FTLD. Nature 626:1073–1083. https://doi.org/10.1038/s41586-024-07042-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Iturria-Medina Y et al (2022) Unified epigenomic, transcriptomic, proteomic, and metabolomic taxonomy of Alzheimer’s disease progression and heterogeneity. Sci Adv 8:eabo6764. https://doi.org/10.1126/sciadv.abo6764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research was funded by the National Natural Science Foundation of China, grant number 82273915.

Author information

Author notes

  1. XiaoTong Hou and JingSi Jiang equally to this work and share first authorship.

Authors and Affiliations

  1. Institute of Medical Innovation and Research, Peking University Third Hospital, No. 49, North Garden Road, HaiDian District, Beijing, China

    XiaoTong Hou, JingSi Jiang & Min Deng

Authors
  1. XiaoTong Hou
    View author publications

    Search author on:PubMed Google Scholar

  2. JingSi Jiang
    View author publications

    Search author on:PubMed Google Scholar

  3. Min Deng
    View author publications

    Search author on:PubMed Google Scholar

Contributions

XTH: literature search, writing—original draft preparation, and writing—review and editing. JSJ: writing—review and editing. MD: study conception and design, and writing—review and editing.

Corresponding author

Correspondence to Min Deng.

Ethics declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hou, X., Jiang, J. & Deng, M. Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis. J Neurol 272, 304 (2025). https://doi.org/10.1007/s00415-025-13028-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00415-025-13028-w

Keywords

Profiles

  1. Min Deng View author profile