Biology subjects

Kanai, T.

Publications and source records attributed to Kanai, T..

3 recordsLinked to original sources

bioRxiv2025

Chiral shift toward D-serine reflects intrathecal inflammation in multiple sclerosis and counteracts motor impairment in a murine model

Multiple sclerosis (MS) is characterized by chronic inflammatory demyelination involving complex interplay between the central nervous and immune systems. Neuroinflammation triggers cellular reorganization requiring O_SCPLOWLC_SCPLOW-serine for sustained syntheses of membrane lipids and nucleic acids, whereas it causes aberrant glutamatergic neurotransmission involving O_SCPLOWDC_SCPLOW-serine. However, significance of serine metabolism in MS pathology remains unexplored. Here we show that serine chiral homeostasis is disrupted in MS and endogenous O_SCPLOWDC_SCPLOW-serine prevents motor deficits caused by inflammatory demyelination. We found in a large cohort study that patients with MS exhibit elevated O_SCPLOWDC_SCPLOW-serine levels and the O_SCPLOWDC_SCPLOW-/total serine ratio in the cerebrospinal fluid at diagnosis. Steric deviation toward O_SCPLOWDC_SCPLOW-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 O_SCPLOWDC_SCPLOW-serine, revealed that endogenous O_SCPLOWDC_SCPLOW-serine synthesis mitigates the progression of motor deficits and suppresses proinflammatory and vascular endothelial pathogenic signaling. Moreover, pre-symptomatic oral supplementation with O_SCPLOWDC_SCPLOW-serine, but not O_SCPLOWLC_SCPLOW-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 O_SCPLOWDC_SCPLOW-serine, our findings reveal an unrecognized significance of O_SCPLOWDC_SCPLOW-serine metabolism in MS and a protective function of O_SCPLOWDC_SCPLOW-serine against neuroinflammation involving disruption of the blood brain barrier, which may present an untapped therapeutic target in MS. One Sentence SummarySerine chiral homeostasis is disturbed in multiple sclerosis and O_SCPLOWDC_SCPLOW-serine mitigates inflammatory demyelination.

neuroscience↗

bioRxiv2024

Serine chirality guides metabolic flow between one-carbon metabolism and neuromodulator synthesis

O_SCPLOWLC_SCPLOW-serine serves as a central metabolic node that integrates glycolytic flux, lipid metabolism, and one-carbon metabolism. In the mature central nervous system, O_SCPLOWLC_SCPLOW-serine is actively stereo-converted to O_SCPLOWDC_SCPLOW-serine, which functions as a neurotransmitter. However, the role of O_SCPLOWDC_SCPLOW-serine in cellular metabolism remains unclear. Here, we show that O_SCPLOWDC_SCPLOW-serine competes with mitochondrial O_SCPLOWLC_SCPLOW-serine transport, thereby suppressing one-carbon metabolism. Metabolomic analysis revealed that O_SCPLOWDC_SCPLOW-serine reduces intracellular glycine and formate levels, indicating inhibition of the initial step of the one-carbon pathway. Molecular dynamics simulations and enzymatic assays revealed that O_SCPLOWDC_SCPLOW-serine has low affinity for serine hydroxymethyltransferase 2 (Shmt2), which catalyzes the first step in mitochondrial one-carbon metabolism, and does not directly inhibit its activity. Instead, membrane transport assays demonstrated that O_SCPLOWDC_SCPLOW-serine competes with mitochondrial O_SCPLOWLC_SCPLOW-serine transport, depleting the substrate of Shmt2. Functionally, under O_SCPLOWLC_SCPLOW-serine poor conditions in vitro and ex vivo, O_SCPLOWDC_SCPLOW-serine inhibited the proliferation of immature and undifferentiated neural cells including glioblastoma stem cells, which depend highly on one-carbon metabolism. Notably, endogenous O_SCPLOWDC_SCPLOW-serine levels were low during early neurodevelopment, but increased with maturation, coinciding with a shift in the transcriptional profiles of serine metabolic enzymes at the cellular level. Given that O_SCPLOWLC_SCPLOW-serine supports neurodevelopment and O_SCPLOWDC_SCPLOW-serine modulates neurotransmission, this developmental shift in serine enantiomer metabolism appears to align with the functional transitions of the maturing nervous system. Thus, our findings reveal that serine chirality can influence mitochondrial substrate availability and one-carbon flux, offering previously unappreciated insight into the stereoselective regulation of cellular metabolism.

developmental biology↗

bioRxiv2019

CLEC-2 suppresses calcification in cultured osteoblasts

Podoplanin is the only counter-receptor of platelet CLEC-2 and is expressing on mature osteoblast, but there is no report on the role of podoplanin and CLEC-2 in calcification. This study aimed to investigate the role of podoplanin binding to CLEC-2 in the calcification of osteoblasts carrying homozygously deleted Pdpn alleles (Pdpn{Delta}/{Delta}) by heterozygously expressing collagen type I alpha 1 promoter (Col1a)-driven Cre recombinase. There were no macroscopic abnormalities in the bone and dentin of Col1a11-Cre;Pdpn{Delta}/{Delta} mice but the coccygeal bone medullary cavity was very narrow. In the quantitative analysis for alizarin red-stained products and alkaline phosphatase activities on the cultured calvarial osteoblasts, the amounts of calcified products and alkaline phosphatase activity of calvarial osteoblasts of both Pdpnfl/fl and Col1a11-Cre;Pdpn{Delta}/{Delta} mice were significantly higher in the calcification medium than in the -mem. Both the amounts of calcified products and alkaline phosphatase activity of calvarial osteoblasts from Pdpnfl/fl mice were significantly lower in the calcification medium with CLEC-2 than without CLEC-2 while there were no significant differences in the amounts of calcified products and alkaline phosphatase activities of calvarial osteoblasts from Col1a11-Cre;Pdpn{Delta}/{Delta} mice with CLEC-2. Platelet CLEC-2 may play a role in regulating the calcification via binding to podoplanin on mature osteoblasts expressing podoplanin in the medullary cavity of a part of the bone.

cell biology↗