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Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis

Jan Spaas, Thibaux Van der Stede (UGent) , Sarah de Jager, Annet van de Waterweg Berends, Assia Tiane, Hans Baelde, Shahid P. Baba, Matthias Eckhardt, Esther Wolfs, Tim Vanmierlo, et al.
(2023) PROGRESS IN NEUROBIOLOGY. 231.
Author
Organization
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.
Keywords
General Neuroscience, Carnosine, Histidine-containing dipeptides, CARNS1, Cuprizone, Experimental autoimmune encephalomyelitis, Multiple sclerosis

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MLA
Spaas, Jan, et al. “Carnosine Synthase Deficiency Aggravates Neuroinflammation in Multiple Sclerosis.” PROGRESS IN NEUROBIOLOGY, vol. 231, Elsevier BV, 2023, doi:10.1016/j.pneurobio.2023.102532.
APA
Spaas, J., Van der Stede, T., de Jager, S., van de Waterweg Berends, A., Tiane, A., Baelde, H., … Derave, W. (2023). Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis. PROGRESS IN NEUROBIOLOGY, 231. https://doi.org/10.1016/j.pneurobio.2023.102532
Chicago author-date
Spaas, Jan, Thibaux Van der Stede, Sarah de Jager, Annet van de Waterweg Berends, Assia Tiane, Hans Baelde, Shahid P. Baba, et al. 2023. “Carnosine Synthase Deficiency Aggravates Neuroinflammation in Multiple Sclerosis.” PROGRESS IN NEUROBIOLOGY 231. https://doi.org/10.1016/j.pneurobio.2023.102532.
Chicago author-date (all authors)
Spaas, Jan, 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, and Wim Derave. 2023. “Carnosine Synthase Deficiency Aggravates Neuroinflammation in Multiple Sclerosis.” PROGRESS IN NEUROBIOLOGY 231. doi:10.1016/j.pneurobio.2023.102532.
Vancouver
1.
Spaas J, Van der Stede T, de Jager S, van de Waterweg Berends A, Tiane A, Baelde H, et al. Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis. PROGRESS IN NEUROBIOLOGY. 2023;231.
IEEE
[1]
J. Spaas et al., “Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis,” PROGRESS IN NEUROBIOLOGY, vol. 231, 2023.
@article{01HGWKZ5A15HAJ0791R2QJB0EK,
  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.}},
  articleno    = {{102532}},
  author       = {{Spaas, Jan and Van der Stede, Thibaux and de Jager, Sarah and van de Waterweg Berends, Annet and Tiane, Assia and Baelde, Hans and Baba, Shahid P. and Eckhardt, Matthias and Wolfs, Esther and Vanmierlo, Tim and Hellings, Niels and Eijnde, Bert O. and Derave, Wim}},
  issn         = {{0301-0082}},
  journal      = {{PROGRESS IN NEUROBIOLOGY}},
  keywords     = {{General Neuroscience,Carnosine,Histidine-containing dipeptides,CARNS1,Cuprizone,Experimental autoimmune encephalomyelitis,Multiple sclerosis}},
  language     = {{eng}},
  pages        = {{14}},
  publisher    = {{Elsevier BV}},
  title        = {{Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis}},
  url          = {{http://doi.org/10.1016/j.pneurobio.2023.102532}},
  volume       = {{231}},
  year         = {{2023}},
}
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