Biology subjects

Nakahara, J.

Publications and source records attributed to Nakahara, J..

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

MECOM promotes leukemia progression and inhibits mast cell differentiation through functional competition with GATA2

MECOM is a nuclear transcription factor essential for the proliferation of hematopoietic stem cells (HSCs) and myeloid leukemia cells. MECOM contains N- and C-terminal zinc finger domains (ZFDs) and binding motifs for the corepressor CtBP to regulate gene expression. Recent studies have shown that germline MECOM variants are associated with thrombocytopenia, radioulnar synostosis, and bone marrow failure, collectively termed MECOM-associated syndromes. Although the mutations are clustered in the C-terminal ZFD, how these mutations affect MECOM function has remained unclear. In addition, the individual genes and pathways regulated by MECOM are less well understood. In this study, we showed that the C-terminal ZFD is a major DNA-binding domain of MECOM and that the disease-associated mutations abolish the DNA-binding ability. We also found that MECOM functionally antagonizes GATA2 through the C-terminal ZFD-mediated DNA binding and CtBP interaction, thereby promoting myeloid leukemogenesis while inhibiting mast cell differentiation. Furthermore, we generated mutant MECOM knockin mice harboring a C-terminal ZFD mutation that recapitulate several features of MECOM-associated syndromes, including HSC and B-cell reduction. Our study demonstrates that C-terminal ZFD mutations are loss-of-function mutations with reduced DNA-binding ability, reveals the critical role of MECOM in inhibiting GATA2, and provides a novel mouse model for MECOM-associated syndromes.

molecular biology↗

bioRxiv2023

Group comparison based on genetic information reveals lineage-specific therapeutic vulnerabilities in acute myeloid leukemia

Cancer is a genetic disease with specific mutations or fusions. Therapies targeting cancer cell-specific essential genes are expected to have efficient anticancer effects with fewer side effects. To explore such cancer cell-specific vulnerabilities, we established a two-group comparison system to predict essential genes in each cancer subtype using the data from the Cancer Dependency Map (DepMap). We applied this analytical method to acute myeloid leukemia (AML) and identified PCYT1A and BCL2L1 as a specific vulnerability in MLL-rearranged AML and TP53-mutated AML, respectively. Interestingly, further investigation revealed that PCYT1A is in fact a critical regulator in monocytic AML including those with MLL-rearrangements, and BCL2L1 is essential in acute erythroid leukemia in which TP53 is frequently mutated. These results highlighted the importance of cell of origin, rather than the genetic aberrations alone, to identify subtype-specific vulnerabilities in AML. The DepMap-based two-group comparison approach could accelerate the discovery of subtype-specific therapeutic targets in diverse cancers.

cancer biology↗