TY - JOUR
T1 - Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis
AU - Spaas, Jan
AU - Van der Stede, Thibaux
AU - de Jager, Sarah
AU - van de Waterweg Berends, Annet
AU - Tiane, Assia
AU - Baelde, Hans
AU - Baba, Shahid P.
AU - Eckhardt, Matthias
AU - Wolfs, Esther
AU - Vanmierlo, Tim
AU - Hellings, Niels
AU - Eijnde, Bert O.
AU - Derave, Wim
N1 - Funding Information:
This work was supported by the Special Research Fund ( BOF R-8156 , Hasselt University, Belgium,) and Research Foundation - Flanders ( 1138520?N , FWO Vlaanderen, Belgium).
Funding Information:
All human brain material has been collected from donors for or from whom a written informed consent for a brain autopsy and the use of the material and clinical information for research purposes had been obtained by The Netherlands Brain Bank (NBB, Netherlands Institute for Neuroscience, Amsterdam; open access www. brainbank.nl). The experiment protocols and methods used for analysing brain samples were conducted with the approval of the NBB and the Medical Ethical Committee of Hasselt University, and carried out according to institutional guidelines. The technical assistance of Anneke Volkaert (Ghent University) and the support from the University Biobank Limburg (UbiLim, prof. Veerle Somers) are greatly appreciated. We thank Flamma (Flamma Group, Chignolo d'Isola, Italy) for providing L-Carnosine. Supplementary Fig S4a, S8a and S9a were created in BioRender.
Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
KW - Carnosine
KW - CARNS1
KW - Cuprizone
KW - Experimental autoimmune encephalomyelitis
KW - Histidine-containing dipeptides
KW - Multiple sclerosis
U2 - 10.1016/j.pneurobio.2023.102532
DO - 10.1016/j.pneurobio.2023.102532
M3 - Article
SN - 0301-0082
VL - 231
JO - Progress in Neurobiology
JF - Progress in Neurobiology
IS - 1
M1 - 102532
ER -