Abstract
Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disease that affects motor neurons and leads to death within 2 to 3 years after the first symptoms manifest. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression in fundamental cellular processes and, post-transcriptionally, the translation levels of target mRNA transcripts. We searched PubMed for studies that examined miRNAs in ALS patients and attempted to group the results in order to find the strongest miRNA candidate for servings as an ALS biomarker. The studies on humans so far have been diverse, yielding considerably heterogeneous results, as they were performed on a wide variety of tissues and subjects. Among the miRNAs that were found consistently deregulated are miR-206, miR-133, miR-149, and miR-338-3p. Additively, the deregulation of some specific miRNAs seems to compose a miRNA expression profile that is specific for ALS. More research is required in order for the scientific community to reach a consensus.
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References
Abe M, Bonini NM (2013) MicroRNAs and neurodegeneration: role and impact. Trends Cell Biol 23:30–36. https://doi.org/10.1016/j.tcb.2012.08.013
Al-Chalabi A, Jones A, Troakes C, King A, Al-Sarraj S, van den Berg LH (2012) The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol 124:339–352. https://doi.org/10.1007/s00401-012-1022-4
Allis CD, Jenuwein T (2016) The molecular hallmarks of epigenetic control. Nat Rev Genet 17:487–500. https://doi.org/10.1038/nrg.2016.59
Anastasiou CA, Yannakoulia M, Kosmidis MH, Dardiotis E, Hadjigeorgiou GM, Sakka P, Arampatzi X, Bougea A, Labropoulos I, Scarmeas N (2017) Mediterranean diet and cognitive health: initial results from the Hellenic Longitudinal Investigation of Ageing and Diet. PloS One 12:e0182048. https://doi.org/10.1371/journal.pone.0182048
Arai T et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611. https://doi.org/10.1016/j.bbrc.2006.10.093
Aschrafi A, Schwechter AD, Mameza MG, Natera-Naranjo O, Gioio AE, Kaplan BB (2008) MicroRNA-338 regulates local cytochrome c oxidase IV mRNA levels and oxidative phosphorylation in the axons of sympathetic neurons. J Neurosci 28:12581–12590. https://doi.org/10.1523/jneurosci.3338-08.2008
Barik S (2008) An intronic microRNA silences genes that are functionally antagonistic to its host gene. Nucleic Acids Res 36:5232–5241. https://doi.org/10.1093/nar/gkn513
Belzil VV, Katzman RB, Petrucelli L (2016) ALS and FTD: an epigenetic perspective. Acta Neuropathol 132:487–502. https://doi.org/10.1007/s00401-016-1587-4
Benigni M, Ricci C, Jones AR, Giannini F, Al-Chalabi A, Battistini S (2016) Identification of miRNAs as potential biomarkers in cerebrospinal fluid from amyotrophic lateral sclerosis patients. NeuroMolecular Med 18:551–560 doi:https://doi.org/10.1007/s12017-016-8396-8
Brett JO, Renault VM, Rafalski VA, Webb AE, Brunet A (2011) The microRNA cluster miR-106b~25 regulates adult neural stem/progenitor cell proliferation and neuronal differentiation. Aging 3:108–124. https://doi.org/10.18632/aging.100285
Brown RH (2009) Medicine. A reinnervating microRNA. Science (New York, NY) 326:1494–1495. https://doi.org/10.1126/science.1183842
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
Butovsky O et al (2012) Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 122:3063–3087. https://doi.org/10.1172/jci62636
Butz H, Liko I, Czirjak S, Igaz P, Korbonits M, Racz K, Patocs A (2011) MicroRNA profile indicates downregulation of the TGFbeta pathway in sporadic non-functioning pituitary adenomas. Pituitary 14:112–124 doi:https://doi.org/10.1007/s11102-010-0268-x
Campbell K, Booth SA (2015) MicroRNA in neurodegenerative drug discovery: the way forward? Expert Opin Drug Discovery 10:9–16. https://doi.org/10.1517/17460441.2015.981254
Campos-Melo D, Droppelmann CA, He Z, Volkening K, Strong MJ (2013) Altered microRNA expression profile in amyotrophic lateral sclerosis: a role in the regulation of NFL mRNA levels. Mol Brain 6:26. https://doi.org/10.1186/1756-6606-6-26
Capitanio D et al (2012) Molecular signatures of amyotrophic lateral sclerosis disease progression in hind and forelimb muscles of an SOD1(G93A) mouse model. Antioxid Redox Signal 17:1333–1350. https://doi.org/10.1089/ars.2012.4524
Cardinali B, Castellani L, Fasanaro P, Basso A, Alema S, Martelli F, Falcone G (2009) MicroRNA-221 and microrna-222 modulate differentiation and maturation of skeletal muscle cells. PloS One 4:e7607 doi:https://doi.org/10.1371/journal.pone.0007607
Chen Y, Wei QQ, Chen XP, Li CY, Cao B, Ou RW, Hadano S, Shang HF (2016) Aberration of miRNAs expression in leukocytes from sporadic amyotrophic lateral sclerosis. Front Mol Neurosci 9:69. https://doi.org/10.3389/fnmol.2016.00069
Chiang HH, Andersen PM, Tysnes OB, Gredal O, Christensen PB, Graff C (2012) Novel TARDBP mutations in Nordic ALS patients. J Hum Genet 57:316–319 doi:https://doi.org/10.1038/jhg.2012.24
Cloutier F, Marrero A, O’Connell C, Morin P Jr (2015) MicroRNAs as potential circulating biomarkers for amyotrophic lateral sclerosis. J Mol Neurosci: MN 56:102–112. https://doi.org/10.1007/s12031-014-0471-8
Coppede F et al (2018) Increase in DNA methylation in patients with amyotrophic lateral sclerosis carriers of not fully penetrant SOD1 mutations. Amyotroph Lateral Sclerosis Frontotemp Degen 19:93–101. https://doi.org/10.1080/21678421.2017.1367401
D’Amico E, Factor-Litvak P, Santella RM, Mitsumoto H (2013) Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis. Free Radic Biol Med 65:509–527. https://doi.org/10.1016/j.freeradbiomed.2013.06.029
Dardiotis E et al (2013a) Intraperitoneal melatonin is not neuroprotective in the G93ASOD1 transgenic mouse model of familial ALS and may exacerbate neurodegeneration. Neurosci Lett 548:170–175. https://doi.org/10.1016/j.neulet.2013.05.058
Dardiotis E, Xiromerisiou G, Hadjichristodoulou C, Tsatsakis AM, Wilks MF, Hadjigeorgiou GM (2013b) The interplay between environmental and genetic factors in Parkinson’s disease susceptibility: the evidence for pesticides. Toxicology 307:17–23. https://doi.org/10.1016/j.tox.2012.12.016
Dardiotis E, Kosmidis MH, Yannakoulia M, Hadjigeorgiou GM, Scarmeas N (2014) The Hellenic Longitudinal Investigation of Aging and Diet (HELIAD): rationale, study design, and cohort description. Neuroepidemiology 43:9–14. https://doi.org/10.1159/000362723
Dardiotis E et al. (2018a) Body mass index and survival from amyotrophic lateral sclerosis: a meta-analysis doi:https://doi.org/10.1212/cpj.0000000000000521
Dardiotis E et al (2018b) Genetic polymorphisms in amyotrophic lateral sclerosis: evidence for implication in detoxification pathways of environmental toxicants. Environ Int 116:122–135. https://doi.org/10.1016/j.envint.2018.04.008
de Andrade HM et al (2016) MicroRNAs-424 and 206 are potential prognostic markers in spinal onset amyotrophic lateral sclerosis. J Neurol Sci 368:19–24. https://doi.org/10.1016/j.jns.2016.06.046
De Felice B, Guida M, Guida M, Coppola C, De Mieri G, Cotrufo R (2012) A miRNA signature in leukocytes from sporadic amyotrophic lateral sclerosis. Gene 508:35–40 doi:https://doi.org/10.1016/j.gene.2012.07.058
De Felice B et al (2014) miR-338-3p is over-expressed in blood, CFS, serum and spinal cord from sporadic amyotrophic lateral sclerosis patients. Neurogenetics 15:243–253. https://doi.org/10.1007/s10048-014-0420-2
Emde A et al (2015) Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS. EMBO J 34:2633–2651. https://doi.org/10.15252/embj.201490493
Evangelou E et al (2010) Non-replication of association for six polymorphisms from meta-analysis of genome-wide association studies of Parkinson’s disease: large-scale collaborative study. Am J Med Genet Part B, Neuropsych Genet:Off Publ Int Soc Psych Genet 153b:220–228. https://doi.org/10.1002/ajmg.b.30980
Freischmidt A, Muller K, Ludolph AC, Weishaupt JH (2013) Systemic dysregulation of TDP-43 binding microRNAs in amyotrophic lateral sclerosis. Acta Neuropathol Commun 1:42. https://doi.org/10.1186/2051-5960-1-42
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
Freischmidt A et al (2015) Serum microRNAs in sporadic amyotrophic lateral sclerosis. Neurobiol Aging 36:2660.e2615–2660.e2620. https://doi.org/10.1016/j.neurobiolaging.2015.06.003
Goljanek-Whysall K, Pais H, Rathjen T, Sweetman D, Dalmay T, Munsterberg A (2012) Regulation of multiple target genes by miR-1 and miR-206 is pivotal for C2C12 myoblast differentiation. J Cell Sci 125:3590–3600. https://doi.org/10.1242/jcs.101758
Goodall EF, Heath PR, Bandmann O, Kirby J, Shaw PJ (2013) Neuronal dark matter: the emerging role of microRNAs in neurodegeneration. Front Cell Neurosci 7:178. https://doi.org/10.3389/fncel.2013.00178
Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004) The Microprocessor complex mediates the genesis of microRNAs. Nature 432:235–240. https://doi.org/10.1038/nature03120
Hardiman O et al (2017) Amyotrophic lateral sclerosis. Nature Rev Dis Primers 3:17071. https://doi.org/10.1038/nrdp.2017.71
Ishtiaq M, Campos-Melo D, Volkening K, Strong MJ (2014) Analysis of novel NEFL mRNA targeting microRNAs in amyotrophic lateral sclerosis. PLoS One 9:e85653. https://doi.org/10.1371/journal.pone.0085653
Kabashi E et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574. https://doi.org/10.1038/ng.132
Kondo A, Iwaki T, Tateishi J, Kirimoto K, Morimoto T, Oomura I (1986) Accumulation of neurofilaments in a sporadic case of amyotrophic lateral sclerosis. Jap J Psychiatry Neurol 40:677–684
Koval ED et al (2013) Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. Hum Mol Genet 22:4127–4135. https://doi.org/10.1093/hmg/ddt261
Kruger R et al (2011) A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease. Neurobiol Aging 32:548.e549–548.e518. https://doi.org/10.1016/j.neurobiolaging.2009.11.021
Kwiatkowski TJ Jr et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science (New York, NY) 323:1205–1208. https://doi.org/10.1126/science.1166066
Maciotta S, Meregalli M, Torrente Y (2013) The involvement of microRNAs in neurodegenerative diseases. Front Cell Neurosci 7:265. https://doi.org/10.3389/fncel.2013.00265
McCarthy JJ (2008) MicroRNA-206: the skeletal muscle-specific myomiR. Biochim Biophys Acta 1779:682–691. https://doi.org/10.1016/j.bbagrm.2008.03.001
Mitropoulos K et al (2017) Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients. Human Genom 11:30. https://doi.org/10.1186/s40246-017-0126-2
Molasy M, Walczak A, Szaflik J, Szaflik JP, Majsterek I (2017) MicroRNAs in glaucoma and neurodegenerative diseases. J Hum Genet 62:105–112. https://doi.org/10.1038/jhg.2016.91
Nicolas A et al (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron 97:1268–1283.e1266. https://doi.org/10.1016/j.neuron.2018.02.027
O'Connell RM, Rao DS, Chaudhuri AA, Baltimore D (2010) Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 10:111–122. https://doi.org/10.1038/nri2708
Pegoraro V, Merico A, Angelini C (2017) Micro-RNAs in ALS muscle: Differences in gender, age at onset and disease duration. J Neurol Sci 380:58–63. https://doi.org/10.1016/j.jns.2017.07.008
Quinlan S, Kenny A, Medina M, Engel T, Jimenez-Mateos EM (2017) MicroRNAs in Neurodegenerative. Dis Int Rev Mol Biol 334:309–343. https://doi.org/10.1016/bs.ircmb.2017.04.002
Rinchetti P, Rizzuti M, Faravelli I, Corti S (2018) MicroRNA metabolism and dysregulation in amyotrophic lateral sclerosis. Mol Neurobiol 55:2617–2630. https://doi.org/10.1007/s12035-017-0537-z
Rodriguez A et al (2007) Requirement of bic/microRNA-155 for normal immune function. Science (New York, NY) 316:608–611. https://doi.org/10.1126/science.1139253
Roshan R, Ghosh T, Scaria V, Pillai B (2009) MicroRNAs: novel therapeutic targets in neurodegenerative diseases. Drug Discov Today 14:1123–1129. https://doi.org/10.1016/j.drudis.2009.09.009
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
Shah P et al (2017) MicroRNA Biomarkers in neurodegenerative diseases and emerging nano-sensors technology. J Move Disord 10:18–28. https://doi.org/10.14802/jmd.16037
Shioya M, Obayashi S, Tabunoki H, Arima K, Saito Y, Ishida T, Satoh J (2010) Aberrant microRNA expression in the brains of neurodegenerative diseases: miR-29a decreased in Alzheimer disease brains targets neurone navigator 3. Neuropathol Appl Neurobiol 36:320–330. https://doi.org/10.1111/j.1365-2990.2010.01076.x
Sokol NS, Xu P, Jan YN, Ambros V (2008) Drosophila let-7 microRNA is required for remodeling of the neuromusculature during metamorphosis. Genes Dev 22:1591–1596. https://doi.org/10.1101/gad.1671708
Sokratous M et al (2016) Deciphering the role of DNA methylation in multiple sclerosis: emerging issues. Auto- immunity Highlights 7:12. https://doi.org/10.1007/s13317-016-0084-z
Sokratous M et al (2018) CpG island methylation patterns in relapsing-remitting multiple sclerosis. J Mol Neurosci: MN 64:478–484. https://doi.org/10.1007/s12031-018-1046-x
Sreedharan J et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science (New York, NY) 319:1668–1672. https://doi.org/10.1126/science.1154584
Sumitha R, Sidhu RJ, Sathyaprabha TN, Nalini A, Raju TR, Alladi PA (2014) Differential expression of microRNA-206 in the gastrocnemius and biceps brachii in response to CSF from sporadic amyotrophic lateral sclerosis patients. J Neurol Sci 345:254–256. https://doi.org/10.1016/j.jns.2014.07.005
Takahashi I et al (2015) Identification of plasma microRNAs as a biomarker of sporadic Amyotrophic Lateral Sclerosis. Mol Brain 8:67. https://doi.org/10.1186/s13041-015-0161-7
Tasca E, Pegoraro V, Merico A, Angelini C (2016) Circulating microRNAs as biomarkers of muscle differentiation and atrophy in ALS. Clin Neuropathol 35:22–30. https://doi.org/10.5414/np300889
Thammaiah CK, Jayaram S (2016) Role of let-7 family microRNA in breast cancer Non-coding RNA. Research 1:77–82. https://doi.org/10.1016/j.ncrna.2016.10.003
Theuns J et al (2014) Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology 83:1906–1913. https://doi.org/10.1212/wnl.0000000000001012
Toivonen JM, Manzano R, Olivan S, Zaragoza P, Garcia-Redondo A, Osta R (2014) MicroRNA-206: a potential circulating biomarker candidate for amyotrophic lateral sclerosis. PLoS One 9:e89065. https://doi.org/10.1371/journal.pone.0089065
Turner MR et al (2013) Mechanisms, models and biomarkers in amyotrophic lateral sclerosis. Amyotroph Tateral Sclerosis Frontotemp Degen 14(Suppl 1):19–32. https://doi.org/10.3109/21678421.2013.778554
Vignier N et al (2013) Distinctive serum miRNA profile in mouse models of striated muscular pathologies. PLoS One 8:e55281. https://doi.org/10.1371/journal.pone.0055281
Vinceti M et al (2017) Pesticide exposure assessed through agricultural crop proximity and risk of amyotrophic lateral sclerosis. Environ Health:Glob Access Sci Source 16(91). https://doi.org/10.1186/s12940-017-0297-2
Wakabayashi K, Mori F, Kakita A, Takahashi H, Utsumi J, Sasaki H (2014) Analysis of microRNA from archived formalin-fixed paraffin-embedded specimens of amyotrophic lateral sclerosis. Acta Neuropathol Commun 2:173. https://doi.org/10.1186/s40478-014-0173-z
Waller R et al (2017) Serum miRNAs miR-206, 143-3p and 374b-5p as potential biomarkers for amyotrophic lateral sclerosis (ALS). Neurobiol Aging 55:123–131. https://doi.org/10.1016/j.neurobiolaging.2017.03.027
Wang L et al (2015) Large-scale assessment of polyglutamine repeat expansions in Parkinson disease. Neurology 85:1283–1292. https://doi.org/10.1212/wnl.0000000000002016
Winton MJ et al (2008) A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro. FEBS Lett 582:2252–2256. https://doi.org/10.1016/j.febslet.2008.05.024
Wu H et al (2012) MiR-20a and miR-106b negatively regulate autophagy induced by leucine deprivation via suppression of ULK1 expression in C2C12 myoblasts. Cell Signal 24:2179–2186. https://doi.org/10.1016/j.cellsig.2012.07.001
Xia L, Zhang Y, Dong T (2016) Inhibition of MicroRNA-221 Alleviates Neuropathic Pain Through Targeting Suppressor of Cytokine Signaling 1. J Mol Neurosci: MN 59:411–420. https://doi.org/10.1007/s12031-016-0748-1
Xu J, Zhao J, Evan G, Xiao C, Cheng Y, Xiao J (2012) Circulating microRNAs: novel biomarkers for cardiovascular diseases. J Mol Med (Berlin, Germany) 90:865–875. https://doi.org/10.1007/s00109-011-0840-5
Yuva-Aydemir Y, Simkin A, Gascon E, Gao FB (2011) MicroRNA-9: functional evolution of a conserved small regulatory RNA. RNA Biol 8:557–564. https://doi.org/10.4161/rna.8.4.16019
Zhang Z et al (2013) Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations. PLoS One 8:e76055. https://doi.org/10.1371/journal.pone.0076055
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MA was supported by grants from the National Institute of Environmental Health Sciences, NIEHS R01ES07331, NIEHS R01ES10563, and NIEHS R01ES020852.
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Dardiotis, E., Aloizou, AM., Siokas, V. et al. The Role of MicroRNAs in Patients with Amyotrophic Lateral Sclerosis. J Mol Neurosci 66, 617–628 (2018). https://doi.org/10.1007/s12031-018-1204-1
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DOI: https://doi.org/10.1007/s12031-018-1204-1