The role of microglial TREM2 in development: A path toward neurodegeneration?

Glia, Journal Year: 2024, Volume and Issue: 72(9), P. 1544 - 1554

Published: June 5, 2024

Abstract The nervous and the immune systems undergo a continuous cross talk, starting from early development continuing throughout adulthood aging. Defects in this talk contribute to neurodevelopmental neurodegenerative diseases. Microglia are resident cells brain that primarily involved bidirectional communication. Among microglial genes, trem2 is key player, controlling functional state of microglia being at forefront many processes require interaction between other components, such as neurons oligodendrocytes. present review focuses on developmental window, describing which TREM2 involved, including modulation synapse formation elimination, control neuronal bioenergetic states well contribution myelination circuit formation. By causing imbalances during these maturation phases, dysfunctional may have striking impact adult brain, making it more sensitive target for insults occurring

Language: Английский

---

Brain development and bioenergetic changes

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 199, P. 106550 - 106550

Published: June 6, 2024

Bioenergetics describe the biochemical processes responsible for energy supply in organisms. When these changes become dysregulated brain development, multiple neurodevelopmental diseases can occur, implicating bioenergetics as key regulators of neural development. Historically, discovery disease affecting individual stages development has revealed critical roles that play generating nervous system. Bioenergetic-dependent disorders include tube closure defects, microcephaly, intellectual disability, autism spectrum disorders, epilepsy, mTORopathies, and oncogenic processes. Developmental timing cell-type specificity determine long-term effects bioenergetic mechanisms on form function. Here, we discuss metabolic progenitor specification, neuronal differentiation (neurogenesis), gliogenesis. In general, transitions between glycolysis oxidative phosphorylation are regulated early oncogenesis, reactive oxygen species (ROS) mitochondrial maturity later differentiation. We also how interface with developmental regulation other elements, including cerebrospinal fluid environment. While questions remain about interplay this review integrates current state known intersections health disease.

Language: Английский

---

From the Structural and (Dys)Function of ATP Synthase to Deficiency in Age-Related Diseases

Life, Journal Year: 2022, Volume and Issue: 12(3), P. 401 - 401

Published: March 10, 2022

The ATP synthase is a mitochondrial inner membrane complex whose function essential for cell bioenergy, being responsible the conversion of ADP into and playing role in cristae morphology organization. enzyme composed 18 protein subunits, 16 nuclear DNA (nDNA) encoded two (mtDNA) encoded, organized domains, FO F1. Pathogenetic variants genes encoding structural subunits or assembly factors are fatal human diseases. Emerging evidence also underlines ATP-synthase neurodegenerative diseases as Parkinson’s, Alzheimer’s, motor neuron such Amyotrophic Lateral Sclerosis. Post-translational modification, epigenetic modulation gene expression level, mechanism transition pore have been deemed neuronal death vivo vitro models In this review, we will explore physiological pathological conditions by referring to recent cryo-EM studies exploring disease models.

Language: Английский

---

Isotope tracing in health and disease

Current Opinion in Biotechnology, Journal Year: 2022, Volume and Issue: 76, P. 102739 - 102739

Published: June 20, 2022

Biochemical characterization of metabolism provides molecular insights for understanding biology in health and disease. Over the past decades, metabolic perturbations have been implicated cancer, neurodegeneration, diabetes, among others. Isotope tracing is a technique that allows tracking labeled atoms within metabolites through biochemical reactions. This has become an integral component contemporary research. measures substrate contribution to downstream indicates its utilization cellular networks. In addition, isotopic labeling data are necessary quantitative flux analysis. Here, we review recent work utilizing study disease, highlight application interrogate subcellular, intercellular, vivo metabolism. We further discuss current challenges opportunities expand utility isotope new research areas.

Language: Английский

---

In preprints: giving the developing brain the energy it needs

Development, Journal Year: 2025, Volume and Issue: 152(2)

Published: Jan. 15, 2025

Metabolism is increasingly appreciated for its active role in tissue development during embryogenesis, particularly discrete instruction brain growth and formation. Catabolic programs are essential the breakdown of nutrients to provide energy anabolic processes that construct macromolecules cell structures required expansion organization (Rajan Fame, 2024). Nutrient availability environmental factors influence bioenergetic state developing cells, instruct cellular tissue-specific niches throughout embryogenesis (Traxler et al., 2021; Andrews Pearson, Intracellular metabolism uses external cues from maternal embryonic environments modify gene expression through epigenetic modifications genomic accessibility (Reid 2017; Sánchez-Ramírez Therefore, assessing relationship between metabolome developmental can insights into mechanisms regulate proliferation, differentiation maturation formation.A recent preprint by Saha colleagues highlights importance nutrient examining effects methionine restriction on cellular- tissue-level changes (Saha 2024 preprint). Methionine, conjunction with other metabolites, interconnected numerous metabolic pathways signaling cascades coordinate function (Sanderson 2019). This study evaluated impact dietary mice day (E) 9.5 gestation or exclusively neurogenesis. The results demonstrate neural progenitors display particular vulnerability, leading downstream decreases neurons astrocytes. Progenitors indicators quiescence suggested differentiation, markers. While restoring levels rescued neuron production, there were continued differences methylation marks, presumably compromised delayed gliogenesis. These findings prompt further questions about how substrates timing fate decisions.In addition availability, a Rodriguez Salazar evaluates mitochondrial dynamics astrocyte morphology rats (Salazar During postnatal development, astrocytes undergo structural functional progress mature state, shifting catabolic support increased demands (Zehnder Marina 2018). balance mitochondria fission, fusion transport coordinating specialized functions (Tábara authors discovered Drp-1-mediated fission enables localization distal higher degrees branching more-complex morphologies. resulting high content establish proper Cx43 gap junction protein abundance an evenly dispersed domain across cortex. Their indicate maturing astrocytes, which mediate complex intercellular, synaptic regulation. Notably, drives glycolytic activity due decreased oxidative phosphorylation efficiency ROS production (Zong 2024; Chen Chan, 2017). Mature have glycolysis influx lactate provides fuel surrounding neurons. morphological complexity supports cortical development.Collectively, these studies highlight unique requirements populations based their rodent Each indicates rewiring accommodate dynamic activities development. Metabolic progenitor cells progeny capacity self-renewal (Zhang 2018; Folmes 2012). consequences production. point response correspond altered quiescence, proliferation impaired neurogenesis gliogenesis, depending duration. focus supportive terminally differentiated later stages astrocytic maturation. Together, clarify stages. change, window, duration perturbation assessments distinct, both manuscripts observe disturbances glial whether In changes, alterations, either tiling territory spatial laminae. Collectively, cell-specific regulates may longitudinal health homeostasis.As describe, affect composition organizational features. Of note, had largest effect weight, compared organs, suggesting neurodevelopmental be vulnerable changes. particular, preferentially impacted, perhaps central nervous system (CNS) (Marina Xiong 2022). proportional decrease types catastrophic long-term (Jourdon 2023; Klingler 2021), also suggest certain pliability fluctuations rescue if reversed relevant windows. Restoration loss after reversal, Drp1 restored fission-regulated morphology. modulate potentially therapeutically target dysfunctional implicated neurological disease. A variety disorders, including autism attention deficit hyperactivity disorder (ADHD), errors metabolism; thus, understanding origins potential treatment valuable (Oyarzábal Pinto Payares 2024).Moving forward, measurements shifts determine bioenergetics affected Mitochondrial biosensors assess real-time, using microscopy (Cambronne 2016; Glancy, 2020). Metabolomic methods magnetic resonance (quantifiable) mass spectrometry (targeted untargeted) comprehensively characterize profiles map pathway isotopic tracers (Johnson Antoniewicz, use gold-standard cutting-edge technologies paired temporal lens will continue illuminate orchestrates programs.

Language: Английский

---

Cytoophidium complexes resonate with cell fates

Cellular and Molecular Life Sciences, Journal Year: 2025, Volume and Issue: 82(1)

Published: Jan. 21, 2025

Abstract Metabolism is a fundamental characteristic of life. In 2010, we discovered that the metabolic enzyme CTP synthase (CTPS) can assemble snake like structure inside cells, which call cytoophidium. Including CTPS, an increasing number enzymes have been found to form cytoophidia in cells. However, distribution and relationship among formed by different remain elusive. Here investigate five cytoophidia, namely Asn1, Bna5, CTPS (i.e. Ura7), Glt1, Prs5 Saccharomyces cerevisiae . We find multiple be assembled into cytoophidium complexes docking one after another. Glt1 tend non-quiescent while are more abundant quiescent cells with Asn1 cytoophidia. Blocking assembly lead phenotype increase Bna5 complex them. also inhibits NAD biosynthesis pathway, includes Sir2. Consistent this result, caused blocking rescued assembly, supplementing nicotinic acid, or overexpressing Our results indicate compositions resonates distinct cell fates. Graphical

Language: Английский

---

Metabolic Atlas of Early Human Cortex Identifies Regulators of Cell Fate Transitions

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Abstract Characterization of cell type emergence during human cortical development, which enables unique cognition, has focused primarily on anatomical and transcriptional characterizations. Metabolic processes in the brain that allow for rapid expansion, but contribute to vulnerability neurodevelopmental disorders, remain largely unexplored. We performed a variety metabolic assays primary tissue stem derived organoids observed dynamic changes core functions, including an unexpected increase glycolysis late neurogenesis. By depleting glucose levels organoids, we increased outer radial glia, astrocytes, inhibitory neurons. found pentose phosphate pathway (PPP) was impacted these experiments leveraged pharmacological genetic manipulations recapitulate glia fate changes. These data identify new role PPP modulating specification generate resource future exploration additional pathways development.

Language: Английский

---

Wolbachia infection confers post-translational modification of glutamic acid decarboxylase and other proteins in D. melanogaster

Microbiology Spectrum, Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

ABSTRACT Wolbachia pipientis is a ubiquitous intracellular bacterium that known for its manipulation of reproduction in arthropod hosts. has also been shown to colonize virtually all somatic tissues, including the brain, but little about interaction between host and these locations. To this end, we studied effects infection on brain Drosophila melanogaster . Using comparative proteomics, uncovered post-translational modification many proteins within head body upon infection, with glutamic acid decarboxylase being modified only. Given enzyme’s role neurotransmitter synthesis, next tested how impacts behaviors gamma aminobutyric (GABA) production We discovered an improved response yeast odors -infected, mated females compared their uninfected counterparts. Gross measurements GABA whole brains showed no detectable change abundance infection. Treatments antagonist indicated behavioral was not GABA-dependent, leaving mechanism behind -mediated changes behavior obscure. multiple protein propose model which drives several metabolic increase survival specialized niche brain. These results give rise new questions Wolbachia–Drosophila relationship, future work will focus through confers changes. IMPORTANCE In order fully understand biology organism, must interactions resident microbes. commonly used study such interactions, molecular hosts are well understood, especially tissues. Here, address knowledge gap by characterizing Our provide first description modifications induced host, unveiling level regulation –host relationship. The be connected or behavior, indicating another enzyme during Altogether, more information ’s tissue spark inquiries into host–bacterium

Language: Английский

---

Glucose oxidation drives trunk neural crest cell development and fate

Journal of Cell Science, Journal Year: 2023, Volume and Issue: 136(16)

Published: Aug. 15, 2023

Bioenergetic metabolism is a key regulator of cellular function and signaling, but how it can instruct the behavior cells their fate during embryonic development remains largely unknown. Here, we investigated role glucose in avian trunk neural crest (NCCs), migratory stem cell population vertebrate embryo. We uncovered that NCCs display oxidation as prominent metabolic phenotype, contrast to what seen for cranial NCCs, which instead rely on aerobic glycolysis. In addition, only one pathway downstream uptake not sufficient NCC development. Indeed, glycolysis, mitochondrial respiration pentose phosphate are all mobilized integrated coordinated execution diverse programs, epithelial-to-mesenchymal transition, adhesion, locomotion, proliferation differentiation, through regulation specific gene expression. absence glucose, OXPHOS fueled by pyruvate failed promote adaptation environmental stiffness, stemness maintenance fate-decision making. These findings highlight need make most potential meet high demands appropriate

Language: Английский

---

Considerations for Using Neuroblastoma Cell Lines to Examine the Roles of Iron and Ferroptosis in Neurodegeneration

Cells, Journal Year: 2024, Volume and Issue: 13(18), P. 1541 - 1541

Published: Sept. 13, 2024

Ferroptosis is an iron-dependent form of programmed cell death that influenced by biological processes such as iron metabolism and senescence. As brain levels increase with aging, ferroptosis also implicated in the development age-related pathologic conditions Alzheimer's disease (AD) related dementias (ADRD). Indeed, inhibitors have been shown to be protective models degenerative disorders like AD/ADRD. Given inaccessibility living human for metabolic studies, goal this work was characterize vitro model understanding how aging availability influence neuronal ferroptosis. First, (SH-SY5Y) mouse (Neuro-2a) neuroblastoma lines were terminally differentiated into mature neurons culturing all-trans-retinoic acid at least 72 h. Despite demonstrating all signs differentiation maturation, including increased expression storage protein ferritin, we discovered conferred resistance both lines. Gene data indicates their capacity protect against iron-mediated oxidative damage augmenting cystine import, subsequently increasing intracellular cysteine levels, promote glutathione production peroxidase activity (GPX). In support hypothesis, found cysteine-depleted media sensitized them GPX4 inhibition, these effects are mitigated supplementation. Such findings important they provide guidance use experimental investigate role neurodegeneration pathologies ADRD.

Language: Английский

---