학술논문
Fibulin-2 is an extracellular matrix inhibitor of oligodendrocytes relevant to multiple sclerosis.
Document Type
Academic Journal
Author
Ghorbani S; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.; Li C; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.; Lozinski BM; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.; Moezzi D; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.; D'Mello C; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.; Dong Y; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.; Visser F; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.; Li H; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.; Silva C; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.; Khakpour M; Division of Medical Sciences, University of Victoria, Victoria, Canada.; Murray CJ; Division of Medical Sciences, University of Victoria, Victoria, Canada.; Tremblay MÈ; Division of Medical Sciences, University of Victoria, Victoria, Canada.; Xue M; Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Yong VW; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.
Source
Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
Subject
Language
English
Abstract
Impairment of oligodendrocytes and myelin contributes to neurological disorders including multiple sclerosis (MS), stroke and Alzheimer's disease. Regeneration of myelin (remyelination) decreases the vulnerability of demyelinated axons, but this repair process commonly fails with disease progression. A contributor to inefficient remyelination is the altered extracellular matrix (ECM) in lesions that remains to be better defined. We have identified fibulin-2 (FBLN2) as a highly upregulated ECM component in lesions of MS and stroke, and in proteome databases of Alzheimer's disease and traumatic brain injury. Focusing on MS, the inhibitory role of FBLN2 was suggested in the experimental autoimmune encephalomyelitis (EAE) model in which genetic FBLN2 deficiency improved behavioral recovery by promoting the maturation of oligodendrocytes and enhancing remyelination. Mechanistically, when oligodendrocyte progenitors were cultured in differentiation media, FBLN2 impeded their maturation into oligodendrocytes by engaging the Notch pathway, leading to cell death. Adeno-associated virus-deletion of FBLN2 in astrocytes improved oligodendrocyte numbers and functional recovery in EAE and generated new myelin profiles after lysolecithin-induced demyelination. Collectively, our findings implicate FBLN2 as a hitherto unrecognized injury-elevated ECM, and a therapeutic target, that impairs oligodendrocyte maturation and myelin repair.