{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:20:35Z","timestamp":1788240035979,"version":"build-2803163510"},"reference-count":42,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS123546"],"award-info":[{"award-number":["NS123546"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Multiple sclerosis (MS) is a neurodegenerative demyelinating disease of the central nervous system. This study aimed to identify micro\u2010RNA (miRNA)\u2013mRNA regulatory networks underlying region\u2010specific molecular mechanisms in white matter and gray matter lesions in progressive MS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Global miRNA and mRNA expression profiling were previously performed on white matter and gray matter lesion tissues from postmortem progressive MS brains. These datasets were integrated using Ingenuity Pathway Analysis (IPA) to identify enriched canonical pathways based on experimentally validated miRNA target genes. Functional effects of selected miRNAs were evaluated in primary oligodendrocyte progenitor cells (OPCs) following miRNA mimic transfection using immunocytochemistry and qPCR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Nine miRNAs were commonly dysregulated in both White Matter lesions (WMLs) and Gray Matter lesions (GMLs). Pathway analysis identified two major downstream pathways\u2014cellular senescence and EIF2 signaling\u2014with opposing predicted activation states (activated in White Matter lesions and inhibited in Gray Matter lesions). Among the shared miRNAs, miR\u201030a and miR\u2010100 exhibited opposing expression patterns, with downregulation in GMLs and upregulation in WMLs, and both were predicted to regulate each pathway. Corresponding target genes of these miRNAs were significantly dysregulated in MS lesions. In primary Oligodendrocyte Progenitor Cells, overexpression of miR\u201030a or miR\u2010100 significantly reduced proliferation and impaired differentiation, accompanied by decreased expression of their respective target genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>These findings identify miRNAs commonly dysregulated across white matter and gray matter lesions in progressive multiple sclerosis. Furthermore, this study also identifies distinct miRNA\u2013mRNA networks and miRNA\u2010driven regulatory mechanisms that contribute to region\u2010specific impairment of oligodendrocyte maturation and remyelination.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70488","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:08:32Z","timestamp":1788239312000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Region Specific miRNA\u2013mRNA Networks in Gray and White Matter Lesions of Progressive Multiple Sclerosis"],"prefix":"10.1002","author":[{"given":"Adya","family":"Sapra","sequence":"first","affiliation":[{"name":"Department of Neurosciences Cleveland Clinic Research  Cleveland Ohio USA"},{"name":"Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine, Case Western Reserve University  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagendra K.","family":"Rai","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Cleveland Clinic Research  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3390-8981","authenticated-orcid":false,"given":"Timothy D.","family":"Niepokny","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Cleveland Clinic Research  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"Courtney","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Cleveland Clinic Research  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajai","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Cleveland Clinic Research  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8502-4455","authenticated-orcid":false,"given":"Ranjan","family":"Dutta","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Cleveland Clinic Research  Cleveland Ohio USA"},{"name":"Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine, Case Western Reserve University  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"issue":"1","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.expneurol.2009.12.020","article-title":"Overcoming Remyelination Failure in Multiple Sclerosis and Other Myelin Disorders","volume":"225","author":"Fancy S. 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