Biology subjects

Sato, C.

Publications and source records attributed to Sato, C..

14 recordsLinked to original sources

bioRxiv2026

Multi-omics definition of the sex-specific glycoproteome of murine tissues

Sex-specific differences in the glycoproteome remain poorly defined despite growing evidence that protein glycosylation is a key determinant of sex biology. Here we present a tissue-resolved glycoproteome atlas of adult male and female C57BL/6J mice, integrating transcriptomics, proteomics and glycoproteomics with sialic acid speciation and lectin microarray profiling across 19 tissues. Quantitative analysis of >26,800 protein- and site-specific N-glycoforms from 1,512 glycoproteins revealed highly distinct tissue glycoproteomes shaped by coordinated regulation of protein abundance and glyco-enzyme expression. Multi-omics integration identified strong glycophenotype-enzyme relationships, including control of tissue sialylation by Cmas and Cmah, suggesting rate-limiting roles in glycosylation. Pronounced sex-linked glycophenotypes were observed in salivary gland, liver and kidney, driven by differences in fucosylation, sialylation and protein abundance, whereas the brain glycome was largely conserved between sexes. An interactive online database (https://igcore.cloud/mta/atlas-viewer/) provides a resource for exploring sex-biased glycosylation across mouse tissues.

cell biology↗

bioRxiv2025

Distribution of big tau isoforms in the human central and peripheral nervous system

ObjectiveTau is widely studied in the field of neurodegenerative disease research, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and select central nervous system (CNS) regions. We sought to characterize big tau molecular composition, anatomical distribution, and relevance to neurodegenerative disease. MethodsMass spectrometry was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimers disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord from ALS and controls; and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from young controls and participants stratified by amyloid status and cognitive impairment. ResultsHuman big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were [~]1000-fold higher in brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50 % of the total tau in the periphery and exhibiting considerable regional heterogeneity in the brain ([~] 1 % of total tau). In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD-related pathology. InterpretationBig tau represents a distinct tau population enriched in the PNS and largely uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology.

neuroscience↗

bioRxiv2025

Post-translational modifications distinguish amyloid-β isoform patterns extracted from vascular deposits and parenchymal plaques

Deposition of amyloid-{beta} (A{beta}) aggregates is a core pathological hallmark of both cerebral amyloid angiopathy (CAA) and extracellular parenchymal plaques in Alzheimers disease (AD). While both disease processes share progressive, decades-long deposition of fibrillar A{beta} peptide, they differ in isoform composition. We hypothesized that post-translational modifications (PTMs) on A{beta} would also differ between CAA and parenchymal plaques. Using Lys-N enzymatic digestion followed by quantitative mass spectrometry, we profiled A{beta} isoforms and N-terminus PTMs (aspartic acid isomerization and pyroglutamate formation) across CAA severity and compared them to parenchymal plaque A{beta} in AD. Moderate to severe CAA primarily featured intact N-terminus (A{beta}1-x) ([~]95%) with minimal N-truncated species (A{beta}2-x, A{beta}3pGlu-x, A{beta}4-x), whereas parenchymal plaques displayed diverse N-terminus truncations and PTMs. Increasing CAA severity correlated with a shift from longer, hydrophobic C-terminal isoforms (A{beta}41, A{beta}42, A{beta}43) to shorter, less hydrophobic C-terminal isoforms (A{beta}37, A{beta}38, A{beta}39, A{beta}40). Importantly, moderate and severe CAA displayed minimal isomerization of Asp-1 and Asp-7 residues, which correlated significantly (r > 0.9) with shorter C-terminal isoforms (A{beta}37, A{beta}38, A{beta}39, A{beta}40). These patterns suggest distinct A{beta} aggregation mechanisms in CAA versus parenchymal plaques. We propose that the intact N-terminus found in CAA with limited Asp isomerization is due to its inclusion within the protofibril structure (less disordered and inaccessible to PTMs), unlike the parenchymal plaques, where the N-terminus is more disordered and accessible to PTMs. These biochemical differences may reflect distinct protofibril architectures with potential implications for biomarker development for early CAA detection and therapeutic targeting of vascular and parenchymal A{beta}.

neuroscience↗

bioRxiv2025

Lysyl-phosphatidylglycerol promotes cell-to-cell interaction and biofilm formation of Staphylococcus aureus as a biofilm matrix component

Biofilms formed by Staphylococcus aureus contribute significantly to persistent infections and antibiotic resistance, driven by the unique composition of their extracellular matrix. While previous studies highlighted extracellular DNA, proteins, and polysaccharides as key components, the role of phospholipids in biofilm architecture remains underexplored. This study identifies extracellular phospholipids, including lysyl-phosphatidylglycerol (Lys-PG), phosphatidylglycerol, and cardiolipin (CL), as critical structural elements in S. aureus biofilms. Bacterial phospholipase A1 (PLA1) that cleaves the acyl ester bond at the sn-1 position of phospholipids effectively dispersed pre-formed biofilms and prevented new biofilm formation by hydrolyzing extracellular phospholipids, without affecting bacterial growth or exhibiting cytotoxicity. Microscopy analyses confirmed that PLA1 disrupts membranous nanostructures, including extracellular vesicles and nanofilaments, integral to biofilm stability. Lipidomic analysis revealed an enrichment of Lys-PG and CL in the biofilm matrix. Lys-PG promotes bacterial aggregation by acting as a molecular glue, mediated through electrostatic and hydrophobic interactions. Deletion of the mprF gene, responsible for Lys-PG synthesis, significantly impaired biofilm formation, confirming its essential role. These findings reveal a "moonlighting" function of phospholipids in biofilm architecture, providing insights into biofilm biology and presenting PLA1 as a promising tool for biofilm control. SignificanceBiofilms, dense bacterial communities, pose significant challenges across medical, industrial, and daily life contexts. Understanding their formation mechanisms is crucial for developing effective strategies against them. We investigated biofilm matrix components in S. aureus biofilms, focusing on phospholipids. Our study reveals the presence and significance of Lys-PG in the biofilm matrix, acting as a crucial factor in biofilm formation and maintenance. Through biochemical, lipidomic, and genetic analyses, we demonstrate the role of Lys-PG in facilitating cell-to-cell contacts, contributing to the robustness and thickness of S. aureus biofilms. These findings shed light on the physiological function of extracellular phospholipids in bacterial biofilms and suggest targeting Lys-PG and its synthetic mechanism as a promising strategy for biofilm control.

microbiology↗

bioRxiv2024

Anemonefish use sialic acid metabolism as Trojan horse to avoid giant sea anemone stinging

Anemonefish association with giant sea anemone is an iconic example of mutualistic symbiosis. Living inside the sea anemone without triggering the firing of highly toxic nematocysts present at the surface of sea anemone tentacles provides a unique shelter to the fish, which in return, by its territorial aggressiveness, protects the sea anemone from predators. The mechanisms by which the fish avoids triggering nematocysts discharge remain elusive. One hypothesis proposes that absence of sialic acids might disable nematocysts discharge. Here, we verified four predictions about the role of sialic acids in anemonefish protection: (i) sialic acid levels are lower in anemonefish mucus than in non-symbiotic and sensitive damselfish mucus; (ii) this decrease is specific to mucus and not observed in other organs; (iii) during post-embryonic development the levels of sialic acids are inversely correlated with the level of protection; (iv) the levels of sialic acids are minimal in sea anemone mucus. Taken together, our results allow us to propose a general model, in which anemonefish specifically regulates the level of sialic acids in their mucus to avoid nematocysts discharge. Our analysis also highlights several genes implicated in sialic acid removal as potential targets for allowing protection. Interestingly, our results also suggest that unrelated juveniles of damselfish (Dascyllus trimaculatus) capable to live in proximity with giant sea anemone may use the same mechanisms. Altogether, our data suggest that clownfish use sialic acids as a Trojan horse system to downplay the defenses of the sea anemones and illustrate the convergent tinkering used by fish to allow a mutualistic association with their hosts. Significance statementThe mutualistic relationship between anemonefish and giant sea anemones, where the fish shelter among the anemones tentacles while defending it from predators, is a classic example of symbiosis. However, how the fish avoids triggering the anemones venomous nematocysts has remained a mystery. This study reveals that the fish decrease the levels of sialic acids in their mucus, potentially preventing nematocyst discharge. This finding shed light on the mechanisms underlying this symbiotic relationship. Moreover, the discovery that unrelated damselfish may employ similar strategies underscores the broader significance of convergent adaptations in facilitating similar mutualistic associations in marine fishes.

zoology↗

bioRxiv2023

Single-nucleus multiomic atlas of frontal cortex in amyotrophic lateral sclerosis with a deep learning-based decoding of alternative polyadenylation mechanisms

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two age-related and fatal neurodegenerative disorders that lie on a shared disease spectrum. While both disorders involve complex interactions between neuronal and glial cells, the specific cell-type alterations and their contributions to disease pathophysiology remain incompletely understood. Here, we applied single-nucleus RNA sequencing of the orbitofrontal cortex, a region affected in ALS-FTLD, to map cell-type specific transcriptional signatures in C9orf72-related ALS (with and without FTLD) and sporadic ALS cases. Our findings reveal disease- and cell-type-specific transcriptional changes, with neurons exhibiting the most pronounced alterations, primarily affecting mitochondrial function, protein homeostasis, and chromatin remodeling. A comparison with independent datasets from different cortical regions of C9orf72 and sporadic ALS cases showed concordance in several pathways, with neuronal STMN2 and NEFL showing consistent up-regulation between brain regions and disease subtypes. We also interrogated alternative polyadenylation (APA) as an additional layer of transcriptional regulation, demonstrating that APA events are not correlated with identified gene expression changes. To interpret these events, we developed APA-Net, a deep learning model that integrates transcript sequences with RNA-binding protein expression profiles, revealing cell type-specific patterns of APA regulation. Our atlas illuminates cell type-specific pathomechanisms of ALS/FTLD, providing a valuable resource for further investigation.

neuroscience↗

bioRxiv2023

Endogenous recapitulation of Alzheimers disease neuropathology through human 3D direct neuronal reprogramming

Alzheimers disease (AD) is a neurodegenerative disorder that primarily affects elderly individuals, and is characterized by hallmark neuronal pathologies including extracellular amyloid-{beta} (A{beta}) plaque deposition, intracellular tau tangles, and neuronal death. However, recapitulating these age-associated neuronal pathologies in patient-derived neurons has remained a significant challenge, especially for late-onset AD (LOAD), the most common form of the disorder. Here, we applied the high efficiency microRNA-mediated direct neuronal reprogramming of fibroblasts from AD patients to generate cortical neurons in three-dimensional (3D) Matrigel and self-assembled neuronal spheroids. Our findings indicate that neurons and spheroids reprogrammed from both autosomal dominant AD (ADAD) and LOAD patients exhibited AD-like phenotypes linked to neurons, including extracellular A{beta} deposition, dystrophic neurites with hyperphosphorylated, K63-ubiquitin-positive, seed-competent tau, and spontaneous neuronal death in culture. Moreover, treatment with {beta}- or {gamma}-secretase inhibitors in LOAD patient-derived neurons and spheroids before A{beta} deposit formation significantly lowered A{beta} deposition, as well as tauopathy and neurodegeneration. However, the same treatment after the cells already formed A{beta} deposits only had a mild effect. Additionally, inhibiting the synthesis of age-associated retrotransposable elements (RTEs) by treating LOAD neurons and spheroids with the reverse transcriptase inhibitor, lamivudine, alleviated AD neuropathology. Overall, our results demonstrate that direct neuronal reprogramming of AD patient fibroblasts in a 3D environment can capture age-related neuropathology and reflect the interplay between A{beta} accumulation, tau dysregulation, and neuronal death. Moreover, miRNA-based 3D neuronal conversion provides a human-relevant AD model that can be used to identify compounds that can potentially ameliorate AD-associated pathologies and neurodegeneration.

neuroscience↗

bioRxiv2022

Somatostatin slows Aβ plaque deposition in aged APPNL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner

The molecular underpinnings that govern the endoproteolytic release of the amyloid beta peptide (A{beta}) from the amyloid precursor protein (APP) are now quite well understood. The same cannot be said for the events that precipitate the aggregation and amyloid deposition of A{beta} in Alzheimers disease (AD). The 14-amino-acid cyclic neuroendocrine peptide somatostatin (SST-14) has long been thought of as playing a role, foremost by controlling the expression of the A{beta} clearing enzyme neprilysin, and more recently by directly interacting with A{beta} oligomers. Missing have been in vivo data in a relevant A{beta} amyloidosis model. Here we addressed this shortcoming by crossing AppNL-F/NL-F mice with Sst-deficient mice of identical genetic background to assess if and how the presence of Sst influences key pathological hallmarks of A{beta} amyloidosis that develop in AppNL-F/NL-F mice after 10 months of age. Surprisingly, we found that Sst had no influence on whole brain neprilysin transcript, protein or activity levels, an observation that cannot be accounted for by a compensatory upregulation of the Sst paralog, cortistatin (Cort), that we observed in 15-month-old Sst-deficient mice. The absence of Sst did lead to a subtle but significant increase in the density of cortical A{beta} amyloid plaques. Follow-on western blot analyses of whole brain extracts indicated that Sst interferes with early steps of A{beta} assembly that manifest in Sst null brains through the appearance of SDS-stable smears of 55- 150 kDa. As expected, no effect of Sst on tau steady-state levels or its phosphorylation were observed. Results from this study are easier reconciled with an emerging body of data that point toward Sst affecting A{beta} amyloid plaque formation through direct interference with A{beta} aggregation rather than through its effects on neprilysin expression.

neuroscience↗

bioRxiv2022

Assembly of neuron- and radial glial cell-derived extracellular matrix molecules promotes radial migration of developing cortical neurons

Radial neuronal migration is a key neurodevelopmental event for proper cortical laminar organization. The multipolar-to-bipolar transition, a critical step in establishing neuronal polarity during radial migration, occurs in the subplate/intermediate zone (SP/IZ), a distinct region of the embryonic cerebral cortex. It has been known that the extracellular matrix (ECM) molecules are enriched in the SP/IZ. However, the molecular constitution and functions of the ECM formed in this region remain poorly understood. Here, we identified neurocan (NCAN) as a major chondroitin sulfate proteoglycan in the SP/IZ. NCAN binds to both radial glial cell-derived tenascin-C (TNC) and hyaluronan (HA), a large linear polysaccharide, forming a ternary complex of NCAN, TNC, and HA in the SP/IZ. Developing cortical neurons make contact with the ternary complex during migration. The enzymatic or genetic disruption of the ternary complex impairs radial migration by suppressing the multipolar-to-bipolar transition. Furthermore, both TNC and NCAN promoted the morphological maturation of cortical neurons in vitro. The present results provide evidence for the cooperative role of neuron- and radial glial cell-derived ECM molecules in cortical development.

neuroscience↗

bioRxiv2021

Lower promoter activity of the ST8SIA2 gene has been favored in evolving human collective brains

ST8SIA2 is the main factor regulating expression of the phenotype involved in schizophrenia. Lowered promoter activity of the ST8SIA2 gene is considered to be protective against schizophrenia by conferring tolerance to psychosocial stress. Here, we examined the promoter type composition of anatomically modern humans (AMHs) and archaic humans (AHs; Neanderthals and Denisovans), and compared the promoter activity at the population level (population promoter activity; PPA) between them. In AMHs, the TCT-type, showing the second lowest promoter activity, was most prevalent in the ancestral population of non-Africans. However, the detection of only the CGT-type from AH samples and recombination tracts in AH sequences showed that the CGT- and TGT-types, exhibiting the two highest promoter activities, were common in AH populations. Furthermore, interspecies gene flow occurred into AMHs from AHs and into Denisovans from Neanderthals, influencing promoter-type compositions independently in both AMHs and AHs. The difference of promoter-type composition makes PPA unique in each population. East and Southeast Asian populations show the lowest PPA. This results from the selective increase of the CGC-type, showing the lowest promoter activity, in these populations. Every non-African population shows significantly lower PPA than African populations, resulting from the TCT-type having the highest prevalence in the ancestral population of non-Africans. In addition, PPA reduction is also found among subpopulations within Africa via a slight increase of the TCT-type. These findings indicate a trend toward lower PPA in the spread of AMHs, interpreted as a continuous adaptation to psychosocial stress arising in migration. This trend is considered as genetic tuning for the evolution of collective brains. The inferred promoter-type composition of AHs differed markedly from that of AMHs, resulting in higher PPA in AHs than in AMHs. This suggests that the trend toward lower PPA is a unique feature in AMH spread.

evolutionary biology↗

bioRxiv2021

Chemogenetic activation of nigrostriatal dopamine neurons in freely moving common marmosets

To interrogate particular neuronal pathways in non-human primates under natural and stress-free conditions, we applied designer receptors exclusively activated by designer drugs (DREADDs) technology to common marmosets. We injected adeno-associated virus vectors expressing the excitatory DREADD hM3Dq into the unilateral substantia nigra in three marmosets. Using multi-tracer positron emission tomography imaging, we detected DREADD expression in vivo, which was confirmed in nigrostriatal dopamine neurons by immunohisto-chemistry, and assessed activation of the substantia nigra and dopamine release following agonist administration. The marmosets rotated in a contralateral direction relative to the activated side 30-90 min after consuming food containing the highly potent DREADD agonist deschloroclozapine (DCZ), but not on the following days without DCZ. These results indicate that non-invasive and reversible DREADD manipulation will extend the utility of marmoset as a primate model for linking neuronal activity and natural behavior in various contexts.

neuroscience↗

bioRxiv2019

Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories world-wide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a murine default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

neuroscience↗

bioRxiv2018

The relationship between brain atrophy and cognitive-behavioral symptoms in retired Canadian football players with multiple concussions

Multiple concussions, particularly in contact sports, have been associated with cognitive deficits, psychiatric impairment and neurodegenerative diseases like chronic traumatic encephalopathy. We used volumetric and deformation-based morphometric analyses to test the hypothesis that repeated concussions may be associated with smaller regional brain volumes, poorer cognitive performance and behavioural symptoms among former professional football players compared to healthy controls. This study included fifty-three retired Canadian Football League players, 25 age- and education-matched healthy controls, and controls from the Cambridge Centre for Aging and Neuroscience database for validation. Volumetric analyses revealed greater hippocampal atrophy than expected for age in former athletes with multiple concussions than controls and smaller left hippocampal volume was associated with poorer verbal memory performance. Deformation-based morphometric confirmed smaller bilateral hippocampal volume that were associated with poorer verbal memory performance in athletes. Repeated concussions may lead to greater regional atrophy than expected for age.

neuroscience↗

bioRxiv2017

Tau hyperphosphorylation on T217 in cerebrospinal fluid is specifically associated to amyloid-β pathology

IntroductionModification of CSF tau phosphorylation in AD remains controversial since total-tau and phospho-tau levels measured by immunoassays are highly correlated.\n\nMethodsStoichiometry of phosphorylation of CSF tau was monitored on five sites by mass spectrometry. We compared 50 participants with AD at mild to moderate stages, others tauopathies and controls then confirmed our results in a cohort of 86 participants cognitively normal or with mild cognitive impairment and stratified according to amyloid-{beta} status.\n\nResultsChanges in tau phosphorylation rates were observed in AD participants but not in other tauopathies. T181 appeared slightly hyperphosphorylated in AD. In comparison, T217 phosphorylation, was considerably modified. We demonstrated T217 hyperphosphorylation occurred systematically in amyloid positive participants even at preclinical stage (AUC 0.999). T217 phosphorylation change specificity overpasses other phosphorylated tau sites investigated in this study, but also CSF total-tau and p-tau levels.\n\nDiscussionCSF T217 hyperphosphorylation defines a specific tauopathy status concomitant with {beta}-amyloidosis.

neuroscience↗