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Title: | Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis | Authors: | SPAAS, Jan Van der Stede, Thibaux de Jager, Sarah VAN DE WATERWEG BERENDS, Annet TIANE, Assia Baelde, Hans Baba, Shahid P. Eckhardt, Matthias WOLFS, Esther VANMIERLO, Tim HELLINGS, Niels OP 'T EIJNDE, Bert Derave, Wim |
Issue Date: | 2023 | Publisher: | PERGAMON-ELSEVIER SCIENCE LTD | Source: | PROGRESS IN NEUROBIOLOGY, 231 (Art N° 102532) | Abstract: | Multiple sclerosis (MS) pathology features autoimmune-driven neuroinflammation, demyelination, and failed remyelination. Carnosine is a histidine-containing dipeptide (HCD) with pluripotent homeostatic properties that is able to improve outcomes in an animal MS model (EAE) when supplied exogenously. To uncover if endogenous carnosine is involved in, and protects against, MS-related neuroinflammation, demyelination or remyelination failure, we here studied the HCD-synthesizing enzyme carnosine synthase (CARNS1) in human MS lesions and two preclinical mouse MS models (EAE, cuprizone). We demonstrate that due to its presence in oligodendrocytes, CARNS1 expression is diminished in demyelinated MS lesions and mouse models mimicking demyelination/ inflammation, but returns upon remyelination. Carns1-KO mice that are devoid of endogenous HCDs display exaggerated neuroinflammation and clinical symptoms during EAE, which could be partially rescued by exogenous carnosine treatment. Worsening of the disease appears to be driven by a central, not peripheral immunemodulatory, mechanism possibly linked to impaired clearance of the reactive carbonyl acrolein in Carns1-KO mice. In contrast, CARNS1 is not required for normal oligodendrocyte precursor cell differentiation and (re) myelin to occur, and neither endogenous nor exogenous HCDs protect against cuprizone-induced demyelination. In conclusion, the loss of CARNS1 from demyelinated MS lesions can aggravate disease progression through weakening the endogenous protection against neuroinflammation. | Notes: | Derave, W (corresponding author), Watersportlaan 2, B-9000 Ghent, Belgium. wim.derave@ugent.be |
Keywords: | Multiple sclerosis;Experimental autoimmune encephalomyelitis;Cuprizone;CARNS1;Histidine-containing dipeptides;Carnosine | Document URI: | http://hdl.handle.net/1942/41836 | ISSN: | 0301-0082 | e-ISSN: | 1873-5118 | DOI: | 10.1016/j.pneurobio.2023.102532 | ISI #: | 001088827200001 | Rights: | 2023 Elsevier Ltd. All rights reserved. | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis.pdf Restricted Access | Published version | 13.26 MB | Adobe PDF | View/Open Request a copy |
Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis.pdf | Non Peer-reviewed author version | 34.3 MB | Adobe PDF | View/Open |
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