Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis

Jan Spaas, Thibaux Van der Stede, Sarah de Jager, Annet van de Waterweg Berends, Assia Tiane, Hans Baelde, Shahid P. Baba, Matthias Eckhardt, Esther Wolfs, Tim Vanmierlo, Niels Hellings, Bert O. Eijnde, Wim Derave*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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 immune-modulatory, 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.
Original languageEnglish
Article number102532
Number of pages14
JournalProgress in Neurobiology
Volume231
Issue number1
DOIs
Publication statusPublished - 1 Dec 2023

Keywords

  • Carnosine
  • CARNS1
  • Cuprizone
  • Experimental autoimmune encephalomyelitis
  • Histidine-containing dipeptides
  • Multiple sclerosis

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