Usiello, A.; Arisumi, K.; Nuzzo, T.; Gilio, L.; Taniguchi, S.; Russo, R.; Motegi, H.; di Vito, R.; Hata, J.; Errico, F.; Hashiguchi, A.; Okano, H.; Furlan, R.; Finardi, A.; Bassi, M. S.; Nakahara, J.; Mita, M.; Kanai, T.; Chambery, A.; Yasui, M.; Centonze, D.; Sasabe, J.

Multiple sclerosis (MS) is characterized by chronic inflammatory demyelination involving complex interplay between the central nervous and immune systems. Neuroinflammation triggers cellular reorganization requiring L-serine for sustained syntheses of membrane lipids and nucleic acids, whereas it causes aberrant glutamatergic neurotransmission involving D-serine. However, significance of serine metabolism in MS pathology remains unexplored. Here we show that serine chiral homeostasis is disrupted in MS and endogenous D-serine prevents motor deficits caused by inflammatory demyelination. We found in a large cohort study that patients with MS exhibit elevated D-serine levels and the D-/total serine ratio in the cerebrospinal fluid at diagnosis. Steric deviation toward D-serine accords with emergence of the intrathecal inflammatory marker oligoclonal bands, and correlates negatively with proinflammatory cytokines. An in vivo animal model of MS, genetically engineered to exhibit distinct metabolic states of D-serine, revealed that endogenous D-serine synthesis mitigates the progression of motor deficits and suppresses proinflammatory and vascular endothelial pathogenic signaling. Moreover, pre-symptomatic oral supplementation with D-serine, but not L-serine, enhances production of extracellular matrices, preserves integrity of the blood brain barrier, attenuates demyelination, and improves motor function. Contrary to the previously recognized neurotoxic nature of D-serine, our findings reveal an unrecognized significance of D-serine metabolism in MS and a protective function of D-serine against neuroinflammation involving disruption of the blood brain barrier, which may present an untapped therapeutic target in MS.