Evaluating the role and therapeutic potential of neuregulin-1 for remyelination in chronic multiple sclerosis

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dc.contributor.authorZiaee, Seyyed Mohyeddin
dc.contributor.examiningcommitteeKauppinen, Tiina (Pharmacology and Therapeutics)
dc.contributor.examiningcommitteeDa Silva, Robin (Physiology and Pathophysiology)
dc.contributor.examiningcommitteeThompson, Peter (Physiology and Pathophysiology)
dc.contributor.supervisorKarimi-Abdolrezaee, Soheila
dc.date.accessioned2025-01-09T13:55:38Z
dc.date.available2025-01-09T13:55:38Z
dc.date.issued2025-01-08
dc.date.submitted2025-01-03T18:03:25Zen_US
dc.date.submitted2025-01-08T21:17:00Zen_US
dc.degree.disciplinePhysiology and Pathophysiology
dc.degree.levelMaster of Science (M.Sc.)
dc.description.abstractIn in chronic lesions of progressive multiple sclerosis (MS), failure in myelin regeneration and prolonged demyelination lead to permanent neurodegeneration and increased disability. Currently, minimal regenerative treatments are available to promote myelin repair (remyelination) for progressive MS. In acute demyelinating lesions, microglia have remarkable capacity to facilitate remyelination by clearance of cholesterol-rich myelin debris and supporting new oligodendrocytes to remyelinate white matter lesions. However, in chronic demyelinated lesions, microglial cholesterol metabolism and recycling process is dysregulated, resulting in a dysfunctional myelin-derived lipid-accumulating phenotype that eventually leads to microglial cell death. Currently, the underlying molecular mechanisms that drive microglia dysfunction in progressive MS are not fully understood. We previously reported downregulation of neuregulin-1 (Nrg-1), a key myelination factor, in human secondary progressive MS lesions and lesions of the MS mouse model, experimental auto-immune encephalomyelitis (EAE). Restoring Nrg-1 levels in EAE mice showed positive immunomodulatory effects and promoted a pro-regenerative phenotype in microglia in acute demyelinating lesions. In this study, we demonstrate that persistent dysregulation of Nrg-1 levels contribute to impaired remyelination in chronically demyelinated brain lesions using a cuprizone mouse model of chronic demyelination that models progressive MS and in Nrg-1 conditional knockout mice. Using parallel in vitro and in vivo experiments, we show that therapeutic restoration of Nrg-1 promotes remyelination in chronic demyelinated lesions by enhancing oligodendrogenesis and oligodendrocyte maturation in a microglia-dependent manner. Mechanistically, Nrg-1 treatment revitalizes the innate capacity of microglia for phagocytosis of myelin debris, cholesterol recycling and efflux through activation of LXR and PPARī§ signaling and upregulation of cholesterol transporters. These changes in microglial function improve their survival and provide paracrine support for oligodendrocyte remyelination in chronic demyelinated lesions. Altogether, this study, for the first time, links dysregulation of Nrg-1 to remyelination failure in chronic demyelinated lesions, and demonstrates the therapeutic potential of Nrg-1 to augment the ability of microglia for remyelination in progressive MS.
dc.description.noteFebruary 2025
dc.description.sponsorshipUniversity of Manitoba Graduate Fellowship (UMGF) Rady Faculty of Health Sciences (RFHS) Graduate Studentship
dc.identifier.urihttp://hdl.handle.net/1993/38769
dc.language.isoeng
dc.rightsopen accessen_US
dc.subjectProgressive multiple sclerosis
dc.subjectRemyelination
dc.subjectNeuregulin-1
dc.subjectMicroglia
dc.subjectCuprizone
dc.subjectExperimental autoimmune encephalomyelitis
dc.titleEvaluating the role and therapeutic potential of neuregulin-1 for remyelination in chronic multiple sclerosis
dc.typemaster thesisen_US
local.subject.manitobano
oaire.awardNumber1025767
oaire.awardTitleendMS Doctoral Studentship
project.funder.identifierhttp://dx.doi.org/10.13039/501100000261
project.funder.nameMultiple Sclerosis (MS) Canada
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