Exploring the Tripartite Connection Between miRNA, Major Depression and Multiple Sclerosis and Thereby Proposing Their Early Diagnosis and Possible Therapeutic Modalities
Ashvath Pillai1, Sai Kumar Reddy Pasya2, Vivek Bokka3, Japjee Parmar4, Megha Tiwari5, Sai Prasad6, Satya Bora7, Omer Mohammed8, Venkateshwaran Vijayanarasimhan9, Sambuddha Karmarkar10, Nimrah Fathima11
1SSPM medical college and Lifetime Hospital, 2Kansas university of medical centre, 3Grant medical college, Mumbai, 4Government medical college Amritsar, 5SIES college of arts,science and commerce, 6S Nijalingappa medical college Bagalkot, 7Dr.Pinnamaneni Siddhartha Institute of medical sciences and Research foundation, 8GMC calicut, 9Mayo clinic,Florida, 10Raigand Government medical college and hospital, west bengal, 11Ayaan Institute Of Medical Sciences, Kanaka Mamidi, Telangana, India.
Background:
Major depressive disorder (MDD) and multiple sclerosis (MS) usually find comorbidity and share neuro-immune dysregulation. Mounting evidence suggests that epigenetic mechanisms—mainly comprising miRNAs, DNA-(hydroxy)methylation, and lncRNA-driven chromatin changes—might be a common mechanistic axis. However, there has never been any attempt at integrating the extent to which these phenomena occur, their consistency, as well as their translational relevance across both disorders into one synthesis.
Design/Methods:
MEDLINE, EMBASE, Scopus, and Web of Science were searched up to 30 April 2024 for studies assessing miRNA expression, DNA/5-hmC marks, histone/chromatin modifications, or lncRNA/ceRNA networks in MDD or MS. Two reviewers independently screened the records, extracted data using a standardised form, and assessed the quality of included studies with the Newcastle–Ottawa Scale (NOS). Due to the heterogeneity in biospecimen and analytical platforms, a narrative synthesis was pursued.
Results:
28 primary studies were included. In MDD, the upregulation of miR-221, miR-124-3p, and brain-specific miR-132 was consistently related to impaired Wnt2/CREB/BDNF signalling and limbic network dysfunction. In MS, down-regulation of miR-181a-5p (AUC 0.78), promoter hyper-methylation of MIR21 (relapsing-remitting subtype), and dynamic changes in miR-155 and miR-326 post-disease-modifying therapy were of diagnostic and prognostic value. Cross-disorder convergence entailed the up-regulation of pro-inflammatory miRNAs (miR-155, miR-221), repression of neurotrophic miRNAs (miR-181a, miR-124-3p) and sex-biased silencing of the DLK1-DIO3 imprinted cluster. Functional studies implied the BHMT-betaine methyl cycle, dimethyl-fumarate-mediated chromatin reopening and lncRNAs HOTAIR and MALAT1 as potential upstream regulators.
Conclusions:
Essentially for deregulated diseases such as MDD and MS, miRNAs, under the supervision of DNA/5-hmC marks and lncRNA-driven chromatin architecture, constitute epigenetic convergence. These stage- and treatment-specific signatures provide an instant promise for biomarkers, whereas mechanistic data identify the upstream targets for the next epigenetic therapies. Therefore, they require prospective multi-omic longitudinal and interventional investigations to determine causality and speed the clinical translation.
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