Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis

Spaas, J.; Van der Stede, T.; de Jager, S.; van de Waterweg Berends, A.; Tiane, A.; Baelde, H.; Baba, S. P.; Eckhardt, M.; Wolfs, E.; Vanmierlo, T.; Hellings, N.; Eijnde, B. O.; Derave, W.

doi:10.1101/2023.03.30.534899

bioRxiv · 10.1101/2023.03.30.534899

Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis

Spaas, J.·Van der Stede, T.·de Jager, S.·van de Waterweg Berends, A.·Tiane, A.·Baelde, H.·Baba, S. P.·Eckhardt, M.·Wolfs, E.·Vanmierlo, T.·Hellings, N.·Eijnde, B. O.·Derave, W.

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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, the presence of CARNS1 and endogenous HCDs does not protect against cuprizone-induced demyelination, and is not required for normal oligodendrocyte precursor cell differentiation and (re)myelin to occur. Exogenously administered carnosine is not effective in blunting demyelination or accelerating remyelination. In conclusion, we show that CARNS1 is diminished in demyelinated MS lesions, which may have detrimental effects on disease progression through weakening the endogenous protection against neuroinflammation.

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Spaas, J., Van der Stede, T., de Jager, S., van de Waterweg Berends, A., Tiane, A., Baelde, H., Baba, S. P., Eckhardt, M., Wolfs, E., Vanmierlo, T., Hellings, N., Eijnde, B. O., Derave, W.. 2023-03-31. Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis. https://doi.org/10.1101/2023.03.30.534899

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