Biology subjects

Hattori, A.

Publications and source records attributed to Hattori, A..

5 recordsLinked to original sources

bioRxiv2026

Structural insights and mechanistic inhibition of Plasmodium falciparum dihydroorotate dehydrogenase by newly identified chemotypes

Resistance to frontline antimalarial drugs continues to threaten malaria control, highlighting the need for new chemotypes. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes a key step in de novo pyrimidine biosynthesis and remains a validated antimalarial target. Although the PfDHODH inhibitor DSM265 advanced to clinical development, resistance-associated mutations highlight the need for structurally distinct inhibitors. Here, we report the discovery and structural characterization of PfDHODH inhibitors identified through target-based high-throughput screening of 432,592 compounds. Primary hits were evaluated by dose-response assays against asexual blood-stage parasites, mammalian mitochondrial toxicity assays, and HepG2 cytotoxicity profiling, yielding 348 hits. Seven representative compounds were prioritized based on efficacy against PfDHODH and orthologs from P. vivax and P. berghei, and their X-ray co-crystal structures revealed distinct binding modes within the active site. Ferulenol exhibited sub-micromolar inhibition of recombinant PfDHODH (rPfDHODH) and rPvDHODH, together with potent blood-stage activity, with its prenylated tail contributing additional hydrophobic interactions. Compound 2 showed the highest potency across the tested DHODH enzymes but reduced selectivity for PfDHODH, potentially due to its distinct binding orientation and furylmethyl substituent. Comparative structural analyses with DSM265 identified binding-site features that may guide the design of next-generation PfDHODH inhibitors with improved potency and selectivity.

microbiology↗

bioRxiv2024

Induction of the aggresome and insoluble tau aggregation using an optogenetic tool

Tauopathy is a spectrum of diseases characterized by fibrillary tau aggregate formation in neurons and glial cells in the brain. Tau aggregation originates in the brainstem and entorhinal cortex and then spreads throughout the brain in Alzheimers disease (AD), which is the most prevalent type of tauopathy. Understanding the mechanism by which locally developed tau pathology propagates throughout the brain is crucial for comprehending AD pathogenesis. Therefore, a novel model of tau pathology that artificially induces tau aggregation in targeted cells at specific times is essential. This study describes a novel optogenetic module, OptoTau, which is a human tau with the P301L mutation fused with a photosensitive protein CRY2olig, inducing various forms of tau according to the temporal pattern of blue light illumination pattern. Continuous blue light illumination for 12 h to Neuro2a cells that stably express OptoTau (OptoTauKI cells) formed clusters along microtubules, many of which eventually accumulated in aggresomes. Conversely, methanol-resistant tau aggregation was formed when alternating light exposure and darkness in 30-min cycles for 8 sets per day were repeated over 8 days. Methanol-resistant tau was induced more rapidly by repeating 5-min illumination followed by 25-min darkness over 24 h. These results indicate that OptoTau induced various tau aggregation stages based on the temporal pattern of blue light exposure. Thus, this technique exhibits potential as a novel approach to developing specific tau aggregation in targeted cells at desired time points. SignificanceThis study developed an approach to manipulate tau aggregation in a blue light-dependent manner using cells that stably express OptoTau, which is an optogenetic tool based on the CRY2olig module. Tau accumulation in aggresomes or stable tau aggregation were selectively induced by blue light illumination conditions. These results are crucial as they provide a new technological basis for establishing a singular point of tau aggregation in specific targeted cells at a particular time.

biophysics↗

bioRxiv2023

Role of Immature Choroid Plexus in the Pathology of Autism Spectrum Disorder

During gestation, the choroid plexus (ChP) produces protein-rich cerebrospinal fluid and matures prior to brain development. It is assumed that ChP dysfunction has a profound effect on developmental neuropsychiatric disorders, such as Autism Spectrum Disorder (ASD). However, the mechanisms linking immature ChP to the onset of ASD remain unclear. In this study, we found that ChP-specific CAMDI-knockout mice developed an immature ChP, alongside decreased multiciliogenesis and expression of differentiation marker genes following disruption of the cerebrospinal fluid barrier. These mice exhibited ASD-like behaviors, including impaired socialization with delayed critical period. Additionally, administration of Metformin, an FDA-approved drug, before the critical period achieved ChP maturation and restored social behaviors. Furthermore, ASD model mice and ASD patient-derived organoids developed immature ChP. These results indicate towards involvement of immature ChP in the pathogenesis of ASD and suggest the targeting of functional maturation of ChP as a therapeutic strategy for ASD.

neuroscience↗

bioRxiv2021

Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height

Adult men are, on average, [~]13 cm taller than adult women. Although previous studies have suggested a significant contribution of sex chromosomal genes to sexual dimorphism in height, all attempts to identify a male-specific growth gene have failed. In the present study, we analyzed transcripts from cartilage tissues, and found that the expression of SHOX, a growth-promoting gene in the pseudoautosomal region on the X and Y chromosomes, was lower in females than in males. DNA methylation analyses showed that SHOX has some characteristics of genes subjected to X chromosome inactivation (XCI). These findings indicate that sex difference in human height is mainly ascribed to incomplete spreading of XCI on a pseudoautosomal gene. More importantly, RT-PCR of fibroblast clones revealed XCI-independent random clonal monoallelic expression of SHOX. We presume that during eutherian evolution, SHOX translocated from an autosome to the proto-sex chromosome without losing the epigenetic memory of random clonal monoallelic expression and subsequently underwent partial XCI. This study provides a novel model of epigenetic gene regulation leading to phenotypic diversity in humans.

genetics↗

bioRxiv2018

Continuous in vivo metabolism by NMR

Dense time-series metabolomics data are essential for unraveling the underlying dynamic properties of metabolism. Here we extend high-resolution-magic angle spinning (HR-MAS) to enable continuous in vivo monitoring of metabolism by NMR (CIVM-NMR) and provide analysis tools for these data. First, we reproduced a result in human chronic lymphoid leukemia cells by using isotope-edited CIVM-NMR to rapidly and unambiguously demonstrate unidirectional flux in branched-chain amino acid metabolism. We then collected untargeted CIVM-NMR datasets for Neurospora crassa, a classic multicellular model organism, and uncovered dynamics between central carbon metabolism, amino acid metabolism, energy storage molecules, and lipid and cell wall precursors. Virtually no sample preparation was required to yield a dynamic metabolic fingerprint over hours to days at ~4-min temporal resolution with little noise. CIVM-NMR is simple and readily adapted to different types of cells and microorganisms, offering an experimental complement to kinetic models of metabolism for diverse biological systems.

systems biology↗