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    Topic review

    MicroRNAs, Multiple Sclerosis, and Depression

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    Submitted by: Hsiuying Wang

    Definition

    Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects the brain and spinal cord. There are several disease courses in MS including relapsing–remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). Up to 50% of MS patients experience depressive disorders. Major depression (MD) is a serious comorbidity of MS. Many dysfunctions including neuroinflammation, peripheral inflammation, gut dysbiosis, chronic oxidative and nitrosative stress, and neuroendocrine and mitochondrial abnormalities may contribute to the comorbidity between MS and MD. In addition to these actions, medical treatment and microRNA (miRNA) regulation may also be involved in the mechanisms of the comorbidity between MS and MD.

    1. MicroRNA

    miRNA is a small non-coding RNA with a length of about 21–24 nucleotides. It has important functions in cell differentiation, development, cell cycle regulation, and apoptosis. miRNAs can regulate up to 30% of the protein-coding genes in the human genome [1], and it is well known that they are involved in the development of many diseases. Strong evidence revealed that in cancer cells, miRNAs were dysregulated due to various mechanisms including abnormal transcriptional controls of miRNAs, dysregulated epigenetic changes, and defects in the miRNA biogenesis pathway [2]. As a result, miRNAs are good biological biomarkers of various cancers, and many bioinformatics tools have been developed to predict miRNA biomarkers of cancers [3][4][5][6][7][8].

    One of the main barriers to cancer chemotherapy is the drug resistance problem. miRNAs were also shown to contribute to the development of resistance against chemotherapy [9]. In addition to cancers, abnormal miRNA expression also contributes to neurological and psychiatric diseases such as frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, spinal muscular atrophy, amyotrophic lateral sclerosis, and anti-NMDA receptor encephalitis [10][11][12][13][14][15]. miRNA biomarkers have been used to explore the association between different diseases and the association between vaccination and diseases [15][16][17].

    2. MicroRNA Biomarkers

    Many common miRNA biomarkers of both diseases are presented in Table 1. Nevertheless, there may be more common miRNA biomarkers of MS and MD than those listed in Table 1.

    Table 1. The common miRNA biomarkers of MS and MD are provided. The expression information with parentheses means the expression information after the treatment of the drug.

    miRNA MS miRNA
    Expression
    MS References MD miRNA
    Expression
    MD References
    miR-125a ↑,
    ↓(Natalizumab)
    [18][19][20][21][22][23][24] ↓,↑,
    ↓(Escitalopram)
    [25][26][27][28]
    miR-146b [18][29] ↓(Escitalopram),
    ↑(Duloxetine)
    [25]
    [30]
    miR-200c [18][29] [31]
    miR-328 ↓,↑ [18][24][29][32] [28][33]
    miR-199a ↑,↓ [18][29][32][34][35] [28][36]
    miR-152 ↓,↑ [18] ↑(Lithium) [37]
    miR-650 [29][38] [28][31]
    miR-326 ↑,
    ↓(Natalizumab)
    [19][29][39][40][41] [42]
    miR-142 ↑,↓ [29][35][43] ↓,↑ [44][45]
    miR-21 ↑,↓ [29][46] [47]
    miR-27a [22][29][48] [25][44][49]
    miR-193a [29][50] [51]
    miR-15a [29][52] [53]
    miR-130a [29] [44]
    miR-22 [29][43] ↓,↑(Escitalopram) [49][51][54]
    miR-320 [20][29][55] [28][56]
    miR-214 ↑,↓ [29][48] [57]
    miR-184 [22][29][58] ↓,↑ [27][59][60]
    miR-139 [29][38] [28][61][62][63]
    miR-23b [29][64] [45]
    miR-487b [29][38] [26][31]
    miR-181c [29][65][66] ↓,↑ [27][31][60]
    miR-340 ↓,↑ [29][67][68] [69]
    miR-629 [29][70] ↑,↑(Escitalopram) [49][51][54]
    miR-148a [29][67] [49][71]
    miR-28 [29]   [49]
    miR-195 [29] [63]
    miR-497 ↑,↓ [29][50][70] [44]
    miR-135a [29][38][72] [31][69]
    miR-204 [29][38][72] [73]
    miR-660 ↑,↓ [29][38][43][72] [44]
    miR-30a ↑,↓ [22][24][29][32][38][70][72] [28][74]
    miR-365 ↑,↓ [29][32] [31]
    miR-532 ↑,↓ [29][75] ↓,↑(Escitalopram) [25][28][76]
    miR-126 [29][50][77] ↓,↓(Escitalopram) [25][26][49]
    Let-7c ↑,
    ↓(natalizumab)
    [23][29][38][72] [78]
    miR-20b ↑,↓ [24][29][40] [44]
    miR-30d [29][79] ↑,↑(Escitalopram) [54][80]
    miR-9 [22][29][81] [26]
    miR-219 [22][29] [82]
    miR-338 [22][29] [76]
    miR-642 ↓,
    ↑(natalizumab)
    [23][29] [44]
    miR-181b [29][83] ↓(Escitalopram) [25]
    miR-18a [29][40] ↑,↑(Duloxetine) [27][60][84]
    miR-190 [29][38] [44]
    miR-213 [29][38] [85]
    miR-330 [29][35] [28][36]
    miR-151 [29][38] ↓(Escitalopram) [25]
    miR-140 [29][38] ↑(Escitalopram) [54][60]
    miR-146a ↑,↓ [21][22][24][29][32][43][86] ↓,
    ↑(Duloxetine),
    ↓(Escitalopram)
    [25][30][31][44]
    miR-223 ↑,↓ [21][22][29][87] ↑,↓(Escitalopram) [25][28]
    miR-30c [21][34] [26][88]
    miR-155 ↑,↓ [21][22][29] ↑,↓,↑(Lithium) [28][31][37][44][49]
    miR-124 [21][22] ↑,↓,↓(Duloxetine) [31][76][84][89][90][91]
    miR-34a ↑,↓ [22][29][34][50] ↑,↑(Lithium) [28][37][92]
    miR-19a ↑,↓ [34][43] [93]
    miR-21 ↑,↓ [32][86] ↑,↓ [47][51]
    miR-22 [43][94] ↓,↑(Escitalopram) [51][54]
    miR-486 [43][50] [76]
    miR-451a ↓,↑ [43][87] [28][56]
    let-7b ↓,↑ [24][43][95] [78]
    miR-320b [43][96] [51]
    miR-122 ↓,↑ [38][43][72] [51]
    miR-215 [43][83] [97]
    miR-26a ↓,↑ [41][43] ↑(Escitalopram),
    ↓(Escitalopram)
    [25][54]
    miR-15b [43][87] ↑,↓ [28][98]
    miR-221 [24][83] [49]

    Most of the miRNAs in Table 1 are reviewed as follows. The miRNA expression was obtained from the peripheral blood mononuclear leukocytes from 10 Chinese MS patients and 10 healthy controls [18]. Then the study was validated independently using real-time polymerase chain reaction (PCR) in the second cohort of 40 MS patients and 40 controls. The levels of miR-125a, miR-146b, and miR-200c were elevated in these MS patients, whereas miR-328, miR-199a, and miR-152 were decreased. The active lesions in the brains of the early stages of MS patients contain many inflammatory cells and macrophages. Moreover, the cerebrospinal fluid (CSF) of MS patients bearing active demyelinating lesions had abnormally high miR-125a-3p levels [19]. Interleukin 17 (IL-17)-producing T helper cells (TH-17 cells) were shown to be implicated with MS [99]. miR-326 was associated with the pathogenesis of MS by regulating TH-17 differentiation [39]. The protein urocortin 1 (Ucn1) is most abundantly expressed in the midbrain, and depressed suicide completers have upregulated midbrain Ucn1 expression levels compared with control individuals [100]. miR-326 acted as a molecular switch in the regulation of midbrain Ucn1 expression [42]. A DNA methylation analysis was performed in CD4+ T cells from RRMS, SPMS, and healthy individuals [46]. RRMS patients had lower levels of miR-21 compared to SPMS patients and healthy individuals. Ahmadian-Elmi et al. compared 40 RRMS patients including 20 samples in relapsing and 20 samples in remitting phases with the control group [48]. miR-27a was upregulated in the relapsing phase compared to the remitting phase and healthy individuals, while miR-214 was downregulated in the relapsing phase compared to remitting phase and healthy individuals. miR-15a was downregulated in CD4+ T cells from RRMS patients [52]. miR-320a and miR-125a-5p were significantly upregulated in pediatric MS and adult-onset MS patients [20]. miR-184 could promote oligodendrocyte differentiation that was involved in developing a cell-based therapy for MS [58]. miR-23b, which could halt the progression of experimental autoimmune encephalomyelitis (EAE), was a potential therapeutic target in the amelioration of MS [64].

    Elevated levels of miR-181c were observed in the CSF of MS patients [65]. miR-340 expression in memory CD4+ T-cells increased in MS patients [67][68]. miR-629 was upregulated, but miR-30a-3p and miR-497 were downregulated in CD8+ T cells from peripheral blood samples of RRMS patients [70]. Some differentially expressed miRNAs obtained from several studies were validated in 86 MS patients and 55 controls [32]. miR-328 and miR-30a were upregulated in MS patients, and miR-21, miR-199a, miR-365, and miR-146a were downregulated in MS patients compared with controls. Bioinformatics analysis revealed that miR-532-5p was differentially expressed in RRMS patients, and a digital quantitative PCR method confirmed the downregulation of exosomal miR-532-5p in RRMS relapse patients [75]. Compared with 20 healthy controls, miR-126-5p was upregulated in 17 RRMS patients [77]. Longitudinal analysis revealed that miR-18a and miR-20b were upregulated and predominantly expressed in CD4+ T cells from RRMS patients, whereas miR-326 was downregulated upon natalizumab treatment. An upregulation of miR-9-5p in the relapsing phase of 40 MS patients was observed compared with 11 healthy controls that suggested a possible inducing role of miR-9-5p in the pathway of Th17 cells during MS pathogenesis [81]. MS was characterized by the demyelination of central nervous system neurons. miRNAs play a role in remyelination, contributing to MS, including miR-219, miR-338, miR-125a, miR-27a, miR-146a, miR-9, miR-23, miR-184, miR-124, miR-223, miR-155, miR-30a, miR-34a, miR-326, and miR-27. Compared with the baseline, let-7c and miR-125a-5p were decreased, while miR-642 was increased after 6 and 12 months of the natalizumab therapy [23]. miR-142-5p, miR-199a-5p, and miR-330-3p showed a significant difference between MS patients and controls in terms of the expanded disability status scale score [35]. TaqMan array analysis showed that miR-126, miR-193a, and miR-486 were significantly increased, whereas miR-34a was decreased in CD4+ T cells from peripheral blood mononuclear cells of RRMS patients [50]. miR-124, miR-486a, and miR-532 were significantly decreased in the nucleus accumbens of chronic unpredictable mild stress-induced mice with depression-like behaviors, while miR-388 was significantly upregulated [76]. Exosomal miR-15b-5p and miR-451a were differentially expressed in 25 RRMS patients compared with 11 controls [87]. let-7b-5p is negatively associated with inflammation and disease severity in MS [95]. Upregulation of both miR-326 and miR-26a in the relapsing phase of MS patients compared with remitting phase and healthy controls was observed [41]. Let-7b, miR-20b, miR-30a, miR-125a, miR-146a, miR-221, and miR-328 were differently expressed in MS patients [24].

    The miRNA profiles from active and inactive MS lesions were established by PCR in 16 active and 5 inactive white matter MS brain lesions and 9 control white matter specimens [29]. miRNAs were found at least twice more abundant or less abundant than in normal white matter in inactive lesions (see miRNAs of reference [29] in Table 1). Monocytes–macrophages were shown to influence the inflammatory activity and demyelination in MS. The expression of miRNAs impacting monocyte–macrophage immune function and their communication with brain cells in MS patients was investigated [21]. The levels of miR-146a, miR-223, miR-125a, and miR-30c were increased in both RRMS and PPMS patients compared with controls, and the level of miR-155 was decreased in both PPMS and RRMS patients compared with controls. In addition, reduced levels of miR-124 were observed in PPMS patients compared with controls and RRMS patients.

    Blood samples from 40 RRMS patients and 20 healthy volunteers were investigated [34]. The expression levels of miR-34a, miR-199a, miR-30c, and miR-19a, and the percentage of Th17 and Treg cells were measured. An increased expression of miR-34a, miR-30c, and miR-19a in the relapsing phase and a decreased expression of miR-199a in the remitting phase were observed. A correlation was shown between the four miRNAs, miR-34a, miR-199a, miR-30c, and miR-19a, with different phases of MS, and these miRNAs were involved in differentiation pathways of Th17 cells. The association between the miRNA expression level in CSF and gadolinium-enhancing (Gd+) lesions was investigated to identify the miRNA biomarkers of MS [86]. A total of 28 miRNA candidates in CSF collected from 46 patients with MS (26 Gd+ and 20 Gd− patients) were performed by TaqMan assays and PCR. Increasing levels of miR-21 and miR-146a/b were observed in Gd+ MS patients. miRNAs related to treated MS patients were studied [43]. Eleven RRMS patients were classified into two groups: four untreated patients who had received no treatment with any disease-modifying therapy, and seven treated patients with the immunomodulatory drug IFN-β with at least a 2-year follow-up. PCR analysis showed that 16 miRNAs were differentially expressed in the two groups (see miRNAs of reference [43] in Table 1).

    Lithium (Li) is commonly used in the treatment of bipolar disorder known as manic depression. miR-34a, miR-152, miR-155, and miR-221 were consistently upregulated in 20 lymphoblastoid cell lines with Li treatment at treatment time points day 4 and day 16 [37]. The glutamate receptor, metabotropic 4 (GRM4), that can regulate MD was an attractive target for drug discovery [31]. To investigate GRM4 regulation, an analysis showed that miR-650 and miR-328 were downregulated and upregulated in the blood samples of 18 MD patients compared with healthy controls, respectively [31]. miR-21 was reduced in the white matter of mice with MD [47]. miRNA-15a was increased in the amygdala–Ago2 complex in the mice exposing to chronic stress [53]. β-catenin has been implicated in MD. miR-214-3p was significantly upregulated in the medial prefrontal cortex of chronic social defeat stress mice by targeting β-catenin transcripts [57]. Brain-enriched miRNA-184 is downregulated in older patients with MD [59]. MD patients had significantly increased exosomal miR-139-5p levels when compared with controls [62]. Serum expression levels of miR-23b-3p and miR-142-3p significantly increased in 102 bipolar II disorder patients compared with 118 controls [45]

    The entry is from 10.3390/ijms22157802

    References

    1. Lewis, B.P.; Burge, C.B.; Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005, 120, 15–20.
    2. Peng, Y.; Croce, C.M. The role of MicroRNAs in human cancer. Signal. Transduct Target. Ther. 2016, 1, 15004.
    3. Jansson, M.D.; Lund, A.H. MicroRNA and cancer. Mol. Oncol. 2012, 6, 590–610.
    4. Galka-Marciniak, P.; Urbanek-Trzeciak, M.O.; Nawrocka, P.M.; Dutkiewicz, A.; Giefing, M.; Lewandowska, M.A.; Kozlowski, P. Somatic mutations in miRNA genes in lung cancer-potential functional consequences of non-coding sequence variants. Cancers 2019, 11, 793.
    5. Xian, Q.J.; Zhao, R.L.; Fu, J.J. MicroRNA-527 Induces proliferation and cell cycle in esophageal squamous cell carcinoma cells by repressing pH domain leucine-rich-repeats protein phosphatase 2. Dose Response 2020, 18, 1559325820928687.
    6. Chen, X.H.; Zhang, Z.X.; Ma, Y.; Su, H.X.; Xie, P.; Ran, J.T. LINC02381 promoted cell viability and migration via targeting miR-133b in cervical cancer cells. Cancer Manag. Res. 2020, 12, 3971–3979.
    7. Wang, H. Predicting MicroRNA biomarkers for cancer using phylogenetic tree and microarray analysis. Int. J. Mol. Sci. 2016, 17, 773.
    8. Wang, H. Predicting cancer-related MiRNAs using expression profiles in tumor tissue. Curr. Pharm. Biotechnol. 2014, 15, 438–444.
    9. Si, W.G.; Shen, J.Y.; Zheng, H.L.; Fan, W.M. The role and mechanisms of action of microRNAs in cancer drug resistance. Clin. Epigenetics 2019, 11, 1–24.
    10. Rizzuti, M.; Filosa, G.; Melzi, V.; Calandriello, L.; Dioni, L.; Bollati, V.; Bresolin, N.; Comi, G.P.; Barabino, S.; Nizzardo, M. MicroRNA expression analysis identifies a subset of downregulated miRNAs in ALS motor neuron progenitors. Sci. Rep. 2018, 8, 1–12.
    11. Taguchi, Y.H.; Wang, H. Exploring microRNA biomarker for amyotrophic lateral sclerosis. Int. J. Mol. Sci. 2018, 19, 1318.
    12. Goh, S.Y.; Chao, Y.X.; Dheen, S.T.; Tan, E.K.; Tay, S.S. Role of MicroRNAs in Parkinson’s disease. Int. J. Mol. Sci. 2019, 20, 5649.
    13. Grasso, M.; Piscopo, P.; Talarico, G.; Ricci, L.; Crestini, A.; Tosto, G.; Gasparini, M.; Bruno, G.; Denti, M.A.; Confaloni, A. Plasma microRNA profiling distinguishes patients with frontotemporal dementia from healthy subjects. Neurobiol. Aging 2019, 84, 240e1–240e12.
    14. Magri, F.; Vanoli, F.; Corti, S. mi RNA in spinal muscular atrophy pathogenesis and therapy. J. Cell. Mol. Med. 2018, 22, 755–767.
    15. Wang, H. Phylogenetic analysis to explore the association between anti-NMDA receptor encephalitis and tumors based on microRNA biomarkers. Biomolecules 2019, 9, 572.
    16. Chen, Y.-H.; Wang, H. The association between migraine and depression based on miRNA biomarkers and cohort studies. Curr. Med. Chem. 2020.
    17. Wang, H. Anti-NMDA receptor encephalitis and vaccination. Int. J. Mol. Sci. 2017, 18, 193.
    18. Yang, D.; Wang, W.Z.; Zhang, X.M.; Yue, H.; Li, B.; Lin, L.; Fu, J. MicroRNA expression aberration in Chinese patients with relapsing remitting multiple sclerosis. J. Mol. Neurosci. 2014, 52, 131–137.
    19. Lecca, D.; Marangon, D.; Coppolino, G.T.; Mendez, A.M.; Finardi, A.; Dalla Costa, G.; Martinelli, V.; Furlan, R.; Abbracchio, M.P. MiR-125a-3p timely inhibits oligodendroglial maturation and is pathologically up-regulated in human multiple sclerosis. Sci. Rep. 2016, 6, 1–12.
    20. Nuzziello, N.; Vilardo, L.; Pelucchi, P.; Consiglio, A.; Liuni, S.; Trojano, M.; Liguori, M. Investigating the role of microRNA and transcription factor co-regulatory networks in multiple sclerosis pathogenesis. Int. J. Mol. Sci. 2018, 19, 3652.
    21. Amoruso, A.; Blonda, M.; Gironi, M.; Grasso, R.; Di Francescantonio, V.; Scaroni, F.; Furlan, R.; Verderio, C.; Avolio, C. Immune and central nervous system-related miRNAs expression profiling in monocytes of multiple sclerosis patients. Sci. Rep. 2020, 10, 6125.
    22. Duffy, C.P.; McCoy, C.E. The role of MicroRNAs in repair processes in multiple sclerosis. Cells 2020, 9, 1711.
    23. Chen, C.; Zhou, Y.; Wang, J.; Yan, Y.; Peng, L.; Qiu, W. Dysregulated MicroRNA involvement in multiple sclerosis by induction of T helper 17 cell differentiation. Front. Immunol. 2018, 9, 1256.
    24. Freiesleben, S.; Hecker, M.; Zettl, U.K.; Fuellen, G.; Taher, L. Analysis of microRNA and gene expression profiles in multiple sclerosis: Integrating interaction data to uncover regulatory mechanisms. Sci. Rep. 2016, 6, 34512.
    25. Enatescu, V.R.; Papava, I.; Enatescu, I.; Antonescu, M.; Anghel, A.; Seclaman, E.; Sirbu, I.O.; Marian, C. Circulating plasma micro RNAs in patients with major depressive disorder treated with antidepressants: A pilot study. Psychiatry Investig. 2016, 13, 549.
    26. Rinaldi, A.; Vincenti, S.; de Vito, F.; Bozzoni, I.; Oliverio, A.; Presutti, C.; Fragapane, P.; Mele, A. Stress induces region specific alterations in microRNAs expression in mice. Behav. Brain Res. 2010, 208, 265–269.
    27. Dwivedi, Y. Emerging role of microRNAs in major depressive disorder: Diagnosis and therapeutic implications. Dialogues Clin. Neurosci. 2014, 16, 43–61.
    28. Ferrua, C.P.; Giorgi, R.; da Rosa, L.C.; do Amaral, C.C.; Ghisleni, G.C.; Pinheiro, R.T.; Nedel, F. MicroRNAs expressed in depression and their associated pathways: A systematic review and a bioinformatics analysis. J. Chem. Neuroanat. 2019, 100, 101650.
    29. Junker, A.; Krumbholz, M.; Eisele, S.; Mohan, H.; Augstein, F.; Bittner, R.; Lassmann, H.; Wekerle, H.; Hohlfeld, R.; Meinl, E. MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain 2009, 132, 3342–3352.
    30. Lopez, J.P.; Fiori, L.M.; Cruceanu, C.; Lin, R.; Labonte, B.; Cates, H.M.; Heller, E.A.; Vialou, V.; Ku, S.M.; Gerald, C. MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes. Nat. Commun. 2017, 8, 1–12.
    31. Dwivedi, Y.; Roy, B.; Lugli, G.; Rizavi, H.; Zhang, H.; Smalheiser, N. Chronic corticosterone-mediated dysregulation of microRNA network in prefrontal cortex of rats: Relevance to depression pathophysiology. Transl. Psychiatry 2015, 5, e682.
    32. Quintana, E.; Ortega, F.J.; Robles-Cedeno, R.; Villar, M.L.; Buxo, M.; Mercader, J.M.; Alvarez-Cermeno, J.C.; Pueyo, N.; Perkal, H.; Fernandez-Real, J.M.; et al. miRNAs in cerebrospinal fluid identify patients with MS and specifically those with lipid-specific oligoclonal IgM bands. Mult. Scler. J. 2017, 23, 1716–1726.
    33. Li, J.; Meng, H.; Cao, W.; Qiu, T. MiR-335 is involved in major depression disorder and antidepressant treatment through targeting GRM4. Neurosci. Lett. 2015, 606, 167–172.
    34. Ghadiri, N.; Emamnia, N.; Ganjalikhani-Hakemi, M.; Ghaedi, K.; Etemadifar, M.; Salehi, M.; Shirzad, H.; Nasr-Esfahani, M.H. Analysis of the expression of mir-34a, mir-199a, mir-30c and mir-19a in peripheral blood CD4+T lymphocytes of relapsing-remitting multiple sclerosis patients. Gene 2018, 659, 109–117.
    35. Regev, K.; Healy, B.C.; Paul, A.; Diaz-Cruz, C.; Mazzola, M.A.; Raheja, R.; Glanz, B.I.; Kivisakk, P.; Chitnis, T.; Jagodic, M.; et al. Identification of MS-specific serum miRNAs in an international multicenter study. Neurol. Neuroimmunol. 2018, 5.
    36. Maffioletti, E.; Cattaneo, A.; Rosso, G.; Maina, G.; Maj, C.; Gennarelli, M.; Tardito, D.; Bocchio-Chiavetto, L. Peripheral whole blood microRNA alterations in major depression and bipolar disorder. J. Affect. Disord. 2016, 200, 250–258.
    37. Chen, H.M.; Wang, N.L.; Burmeister, M.; McInnis, M.G. MicroRNA expression changes in lymphoblastoid cell lines in response to lithium treatment. Int. J. Neuropsychoph. 2009, 12, 975–981.
    38. Teuber-Hanselmann, S.; Meinl, E.; Junker, A. MicroRNAs in gray and white matter multiple sclerosis lesions: Impact on pathophysiology. J. Pathol. 2020, 250, 496–509.
    39. Du, C.; Liu, C.; Kang, J.; Zhao, G.; Ye, Z.; Huang, S.; Li, Z.; Wu, Z.; Pei, G. MicroRNA miR-326 regulates T H-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat. Immunol. 2009, 10, 1252.
    40. Ingwersen, J.; Menge, T.; Wingerath, B.; Kaya, D.; Graf, J.; Prozorovski, T.; Keller, A.; Backes, C.; Beier, M.; Scheffler, M.; et al. Natalizumab restores aberrant miRNA expression profile in multiple sclerosis and reveals a critical role for miR-20b. Ann. Clin. Transl. Neurol. 2015, 2, 43–55.
    41. Honardoost, M.A.; Kiani-Esfahani, A.; Ghaedi, K.; Etemadifar, M.; Salehi, M. miR-326 and miR-26a, two potential markers for diagnosis of relapse and remission phases in patient with relapsing-remitting multiple sclerosis. Gene 2014, 544, 128–133.
    42. Aschrafi, A.; Verheijen, J.M.; Gordebeke, P.M.; Loohuis, N.F.O.; Menting, K.; Jager, A.; Palkovits, M.; Geenen, B.; Kos, A.; Martens, G.J.M.; et al. MicroRNA-326 acts as a molecular switch in the regulation of midbrain urocortin 1 expression. J. Psychiatry Neurosci. 2016, 41, 342.
    43. Manna, I.; Iaccino, E.; Dattilo, V.; Barone, S.; Vecchio, E.; Mimmi, S.; Filippelli, E.; Demonte, G.; Polidoro, S.; Granata, A.; et al. Exosome-associated miRNA profile as a prognostic tool for therapy response monitoring in multiple sclerosis patients. FASEB J. 2018, 32, 4241–4246.
    44. Smalheiser, N.R.; Lugli, G.; Rizavi, H.S.; Torvik, V.I.; Turecki, G.; Dwivedi, Y. MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects. PLoS ONE 2012, 7, e33201.
    45. Lee, S.Y.; Lu, R.B.; Wang, L.J.; Chang, C.H.; Lu, T.; Wang, T.Y.; Tsai, K.W. Serum miRNA as a possible biomarker in the diagnosis of bipolar II disorder. Sci. Rep. 2020, 10, 1–10.
    46. Ruhrmann, S.; Ewing, E.; Piket, E.; Kular, L.; Cetrulo Lorenzi, J.C.; Fernandes, S.J.; Morikawa, H.; Aeinehband, S.; Sayols-Baixeras, S.; Aslibekyan, S. Hypermethylation of MIR21 in CD4+ T cells from patients with relapsing-remitting multiple sclerosis associates with lower miRNA-21 levels and concomitant up-regulation of its target genes. Mult. Scler. J. 2018, 24, 1288–1300.
    47. Miguel-Hidalgo, J.J.; Hall, K.O.; Bonner, H.; Roller, A.M.; Syed, M.; Park, C.J.; Ball, J.P.; Rothenberg, M.E.; Stockmeier, C.A.; Romero, D.G.; et al. MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2017, 79, 503–514.
    48. Ahmadian-Elmi, M.; Bidmeshki Pour, A.; Naghavian, R.; Ghaedi, K.; Tanhaei, S.; Izadi, T.; Nasr-Esfahani, M.H. miR-27a and miR-214 exert opposite regulatory roles in Th17 differentiation via mediating different signaling pathways in peripheral blood CD4+ T lymphocytes of patients with relapsing-remitting multiple sclerosis. Immunogenetics 2016, 68, 43–54.
    49. Qi, B.; Fiori, L.M.; Turecki, G.; Trakadis, Y.J. Machine learning analysis of blood microRNA data in major depression: A case-control study for biomarker discovery. Int. J. Neuropsychopharmacol. 2020, 23, 505–510.
    50. Ma, X.; Zhou, J.; Zhong, Y.; Jiang, L.; Mu, P.; Li, Y.; Singh, N.; Nagarkatti, M.; Nagarkatti, P. Expression, regulation and function of microRNAs in multiple sclerosis. Int. J. Med. Sci. 2014, 11, 810–818.
    51. Garbett, K.A.; Vereczkei, A.; Kálmán, S.; Brown, J.A.; Taylor, W.D.; Faludi, G.; Korade, Ž.; Shelton, R.C.; Mirnics, K. Coordinated messenger RNA/microRNA changes in fibroblasts of patients with major depression. Biol. Psychiatry 2015, 77, 256–265.
    52. Lorenzi, J.C.; Brum, D.G.; Zanette, D.L.; de Paula Alves Souza, A.; Barbuzano, F.G.; Dos Santos, A.C.; Barreira, A.A.; da Silva, W.A. miR-15a and 16-1 are downregulated in CD4+ T cells of multiple sclerosis relapsing patients. Int. J. Neurosci. 2012, 122, 466–471.
    53. Volk, N.; Pape, J.C.; Engel, M.; Zannas, A.S.; Cattane, N.; Cattaneo, A.; Binder, E.B.; Chen, A. Amygdalar MicroRNA-15a is essential for coping with chronic stress. Cell Rep. 2016, 17, 1882–1891.
    54. Bocchio-Chiavetto, L.; Maffioletti, E.; Bettinsoli, P.; Giovannini, C.; Bignotti, S.; Tardito, D.; Corrada, D.; Milanesi, L.; Gennarelli, M. Blood microRNA changes in depressed patients during antidepressant treatment. Eur. Neuropsychopharmacol. 2013, 23, 602–611.
    55. Mousavi, S.R.; Tahmasebivand, M.; Khorrami, M.; Ayromlou, H.; Khalili, S.K.; Khorvash, F.; Rikhtegar, R.; Khademi, B.; Bahmanpour, Z.; Emamalizadeh, B. Connection of miR-185 and miR-320a expression levels with response to interferon-beta in multiple sclerosis patients. Mult. Scler. Relat. Disord. 2020, 44, 102264.
    56. Camkurt, M.A.; Acar, Ş.; Coşkun, S.; Güneş, M.; Güneş, S.; Yılmaz, M.F.; Görür, A.; Tamer, L. Comparison of plasma MicroRNA levels in drug naive, first episode depressed patients and healthy controls. J. Psychiatr. Res. 2015, 69, 67–71.
    57. Deng, Z.-F.; Zheng, H.-L.; Chen, J.-G.; Luo, Y.; Xu, J.-F.; Zhao, G.; Lu, J.-J.; Li, H.-H.; Gao, S.-Q.; Zhang, D.-Z. miR-214-3p targets β-catenin to regulate depressive-like behaviors induced by chronic social defeat stress in mice. Cereb. Cortex 2019, 29, 1509–1519.
    58. Afrang, N.; Tavakoli, R.; Tasharrofi, N.; Alian, A.; Naderi Sohi, A.; Kabiri, M.; Fathi-Roudsari, M.; Soufizomorrod, M.; Rajaei, F.; Soleimani, M.; et al. A critical role for miR-184 in the fate determination of oligodendrocytes. Stem Cell Res. Ther. 2019, 10, 112.
    59. Mendes-Silva, A.P.; Fujimura, P.T.; Silva, J.R.D.; Teixeira, A.L.; Vieira, E.M.; Guedes, P.H.G.; Barroso, L.S.S.; Nicolau, M.D.; Ferreira, J.D.R.; Bertola, L.; et al. Brain-enriched MicroRNA-184 is downregulated in older adults with major depressive disorder: A translational study. J. Psychiatr. Res. 2019, 111, 110–120.
    60. Smalheiser, N.R.; Lugli, G.; Rizavi, H.S.; Zhang, H.; Torvik, V.I.; Pandey, G.N.; Davis, J.M.; Dwivedi, Y. MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness. Int. J. Neuropsychoph. 2011, 14, 1315–1325.
    61. Wei, Z.X.; Xie, G.J.; Mao, X.; Zou, X.P.; Liao, Y.J.; Liu, Q.S.; Wang, H.; Cheng, Y. Exosomes from patients with major depression cause depressive-like behaviors in mice with involvement of miR-139-5p-regulated neurogenesis. Neuropsychopharmacology 2020, 45, 1050–1058.
    62. Liang, J.Q.; Liao, H.R.; Xu, C.X.; Li, X.L.; Wei, Z.X.; Xie, G.J.; Cheng, Y. Serum exosome-derived miR-139-5p as a potential biomarker for major depressive disorder. Neuropsychiatr. Dis. Treat. 2020, 16, 2689–2693.
    63. Xu, Y.Y.; Xia, Q.H.; Xia, Q.R.; Zhang, X.L.; Liang, J. MicroRNA-based biomarkers in the diagnosis and monitoring of therapeutic response in patients with depression. Neuropsychiatr. Dis. Treat. 2019, 15, 3583–3597.
    64. Zhang, Y.; Han, J.J.; Liang, X.Y.; Zhao, L.; Zhang, F.; Rasouli, J.; Wang, Z.Z.; Zhang, G.X.; Li, X. miR-23b suppresses leukocyte migration and pathogenesis of experimental autoimmune encephalomyelitis by targeting CCL7. Mol. Ther. 2018, 26, 582–592.
    65. Kramer, S.; Haghikia, A.; Bang, C.; Scherf, K.; Pfanne, A.; Duscha, A.; Kaisler, J.; Gisevius, B.; Gold, R.; Thum, T.; et al. Elevated levels of miR-181c and miR-633 in the CSF of patients with MS: A validation study. Neurol. Neuroimmunol. Neuroinflamm. 2019, 6, e623.
    66. Haghikia, A.; Hellwig, K.; Baraniskin, A.; Holzmann, A.; Decard, B.F.; Thum, T.; Gold, R. Regulated microRNAs in the CSF of patients with multiple sclerosis: A case-control study. Neurology 2012, 79, 2166–2170.
    67. Gao, Y.; Han, D.; Feng, J. MicroRNA in multiple sclerosis. Clin. Chim. Acta 2021, 516, 92–99.
    68. Guerau-de-Arellano, M.; Smith, K.M.; Godlewski, J.; Liu, Y.; Winger, R.; Lawler, S.E.; Whitacre, C.C.; Racke, M.K.; Lovett-Racke, A.E. Micro-RNA dysregulation in multiple sclerosis favours pro-inflammatory T-cell-mediated autoimmunity. Brain 2011, 134, 3578–3589.
    69. Issler, O.; Haramati, S.; Paul, E.D.; Maeno, H.; Navon, I.; Zwang, R.; Gil, S.; Mayberg, H.S.; Dunlop, B.W.; Menke, A.; et al. MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron 2014, 83, 344–360.
    70. Dolati, S.; Marofi, F.; Babaloo, Z.; Aghebati-Maleki, L.; Roshangar, L.; Ahmadi, M.; Rikhtegar, R.; Yousefi, M. Dysregulated network of miRNAs involved in the pathogenesis of multiple sclerosis. Biomed. Pharm. 2018, 104, 280–290.
    71. Belzeaux, R.; Bergon, A.; Jeanjean, V.; Loriod, B.; Formisano-Tréziny, C.; Verrier, L.; Loundou, A.; Baumstarck-Barrau, K.; Boyer, L.; Gall, V. Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode. Transl. Psychiatry 2012, 2, e185.
    72. Fritsche, L.; Teuber-Hanselmann, S.; Soub, D.; Harnisch, K.; Mairinger, F.; Junker, A. MicroRNA profiles of MS gray matter lesions identify modulators of the synaptic protein synaptotagmin-7. Brain Pathol. 2019, 30, 524–540.
    73. Hung, Y.Y.; Huang, Y.L.; Chang, C.; Kang, H.Y. Deficiency in androgen receptor aggravates the depressive-like behaviors in chronic mild stress model of depression. Cells 2019, 8, 1021.
    74. Cattaneo, A.; Suderman, M.; Cattane, N.; Mazzelli, M.; Begni, V.; Maj, C.; D’Aprile, I.; Pariante, C.M.; Luoni, A.; Berry, A.; et al. Long-term effects of stress early in life on microRNA-30a and its network: Preventive effects of lurasidone and potential implications for depression vulnerability. Neurobiol. Stress 2020, 13, 100271.
    75. Selmaj, I.; Cichalewska, M.; Namiecinska, M.; Galazka, G.; Horzelski, W.; Selmaj, K.W.; Mycko, M.P. Global exosome transcriptome profiling reveals biomarkers for multiple sclerosis. Ann. Neurol. 2017, 81, 703–717.
    76. Ma, K.; Zhang, H.; Wei, G.; Dong, Z.; Zhao, H.; Han, X.; Song, X.; Zhang, H.; Zong, X.; Baloch, Z.; et al. Identification of key genes, pathways, and miRNA/mRNA regulatory networks of CUMS-induced depression in nucleus accumbens by integrated bioinformatics analysis. Neuropsychiatr. Dis. Treat. 2019, 15, 685–700.
    77. Chen, J.; Zhu, J.; Wang, Z.; Yao, X.; Wu, X.; Liu, F.; Zheng, W.; Li, Z.; Lin, A. MicroRNAs correlate with multiple sclerosis and neuromyelitis optica spectrum disorder in a Chinese population. Med. Sci. Monit. 2017, 23, 2565–2583.
    78. Gururajan, A.; Naughton, M.; Scott, K.A.; O’connor, R.; Moloney, G.; Clarke, G.; Dowling, J.; Walsh, A.; Ismail, F.; Shorten, G. MicroRNAs as biomarkers for major depression: A role for let-7b and let-7c. Transl. Psychiatry 2016, 6, e862.
    79. Dutta, R.; Chang, A.; Doud, M.K.; Kidd, G.J.; Ribaudo, M.V.; Young, E.A.; Fox, R.J.; Staugaitis, S.M.; Trapp, B.D. Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients. Ann. Neurol. 2011, 69, 445–454.
    80. Mendes, A.P.; Silva, M.; de Souza, E.; Nicolau, S.; Pereira, K.S.; do Nascimento, K.K.F.; Silva, C.M.; Ferreira, M.; Tolentino, G.T.; Araujo, T.; et al. Biological pathways found in common between Alzheimer’s disease and major depression: A study on microrna expression in a systematic review. Alzheimer’s Dement. 2016, 7, P886–P887.
    81. Majd, M.; Hosseini, A.; Ghaedi, K.; Kiani-Esfahani, A.; Tanhaei, S.; Shiralian-Esfahani, H.; Rahnamaee, S.Y.; Mowla, S.J.; Nasr-Esfahani, M.H. MiR-9-5p and miR-106a-5p dysregulated in CD4(+) T-cells of multiple sclerosis patients and targeted essential factors of T helper17/regulatory T-cells differentiation. Iran. J. Basic Med. Sci. 2018, 21, 277–283.
    82. Sun, X.; Song, Z.; Si, Y.; Wang, J.H. microRNA and mRNA profiles in ventral tegmental area relevant to stress-induced depression and resilience. Prog. Neuropsychopharmacol. Biol. Psychiatry 2018, 86, 150–165.
    83. Mohammed, E.M. Environmental influencers, MicroRNA, and multiple sclerosis. J. Cent. Nerv. Syst. Dis. 2020, 12, 1179573519894955.
    84. Pan, B.; Liu, Y. Effects of duloxetine on microRNA expression profile in frontal lobe and hippocampus in a mouse model of depression. Int. J. Clin. Exp. Pathol. 2015, 8, 15454.
    85. Ma, K.; Guo, L.; Xu, A.; Cui, S.; Wang, J.H. Molecular mechanism for stress-induced depression assessed by sequencing miRNA and mRNA in medial prefrontal cortex. PLoS ONE 2016, 11, e0159093.
    86. Munoz-San Martin, M.; Reverter, G.; Robles-Cedeno, R.; Buxo, M.; Ortega, F.J.; Gomez, I.; Tomas-Roig, J.; Celarain, N.; Villar, L.M.; Perkal, H.; et al. Analysis of miRNA signatures in CSF identifies upregulation of miR-21 and miR-146a/b in patients with multiple sclerosis and active lesions. J. Neuroinflamm. 2019, 16, 220.
    87. Ebrahimkhani, S.; Vafaee, F.; Young, P.E.; Hur, S.S.J.; Hawke, S.; Devenney, E.; Beadnall, H.; Barnett, M.H.; Suter, C.M.; Buckland, M.E. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci. Rep. 2017, 7, 14293.
    88. Khandelwal, N.; Dey, S.K.; Chakravarty, S.; Kumar, A. miR-30 family miRNAs Mediate the effect of chronic social defeat stress on hippocampal neurogenesis in mouse depression model. Front. Mol. Neurosci. 2019, 12, 188.
    89. Xu, J.; Wang, R.; Liu, Y.; Liu, D.; Jiang, H.; Pan, F. FKBP5 and specific microRNAs via glucocorticoid receptor in the basolateral amygdala involved in the susceptibility to depressive disorder in early adolescent stressed rats. J. Psychiatr. Res. 2017, 95, 102–113.
    90. Roy, B.; Dunbar, M.; Shelton, R.C.; Dwivedi, Y. Identification of microRNA-124-3p as a putative epigenetic signature of major depressive disorder. Neuropsychopharmacology 2017, 42, 864–875.
    91. He, S.; Liu, X.; Jiang, K.; Peng, D.; Hong, W.; Fang, Y.; Qian, Y.; Yu, S.; Li, H. Alterations of microRNA-124 expression in peripheral blood mononuclear cells in pre-and post-treatment patients with major depressive disorder. J. Psychiatr. Res. 2016, 78, 65–71.
    92. Wan, Y.; Liu, Y.; Wang, X.; Wu, J.; Liu, K.; Zhou, J.; Liu, L.; Zhang, C. Identification of Differential MicroRNAs in Cerebrospinal Fluid and Serum of Patients with Major Depressive Disorder. PLoS ONE 2015, 10, e0121975.
    93. Dwivedi, Y. MicroRNAs in depression and suicide: Recent insights and future perspectives. J. Affect. Disord. 2018, 240, 146–154.
    94. Wang, L.; Qiu, R.; Zhang, Z.; Han, Z.; Yao, C.; Hou, G.; Dai, D.; Jin, W.; Tang, Y.; Yu, X.; et al. The MicroRNA miR-22 Represses Th17 cell pathogenicity by targeting PTEN-regulated pathways. Immunohorizons 2020, 4, 308–318.
    95. Mandolesi, G.; Rizzo, F.R.; Balletta, S.; Bassi, M.S.; Gilio, L.; Guadalupi, L.; Nencini, M.; Moscatelli, A.; Ryan, C.P.; Licursi, V.; et al. The microRNA let-7b-5p is negatively associated with inflammation and disease severity in multiple sclerosis. Cells 2021, 10, 330.
    96. Piket, E.; Zheleznyakova, G.Y.; Kular, L.; Jagodic, M. Small non-coding RNAs as important players, biomarkers and therapeutic targets in multiple sclerosis: A comprehensive overview. J. Autoimmun. 2019, 101, 17–25.
    97. Yoshino, Y.; Roy, B.; Dwivedi, Y. Differential and unique patterns of synaptic miRNA expression in dorsolateral prefrontal cortex of depressed subjects. Neuropsychopharmacology 2021, 46, 900–910.
    98. Zhang, Y.; Zhu, X.; Bai, M.; Zhang, L.; Xue, L.; Yi, J. Maternal deprivation enhances behavioral vulnerability to stress associated with miR-504 expression in nucleus accumbens of rats. PLoS ONE 2013, 8, e69934.
    99. Tzartos, J.S.; Friese, M.A.; Craner, M.J.; Palace, J.; Newcombe, J.; Esiri, M.M.; Fugger, L. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol. 2008, 172, 146–155.
    100. Kozicz, T.; Tilburg-Ouwens, D.; Faludi, G.; Palkovits, M.; Roubos, E. Gender-related urocortin 1 and brain-derived neurotrophic factor expression in the adult human midbrain of suicide victims with major depression. Neuroscience 2008, 152, 1015–1023.
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