Alzheimer’s disease protective allele of Clusterin modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication DOI Creative Commons
Xiaojie Zhao, Yan Li, Siwei Zhang

et al.

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: May 3, 2025

Abstract Background Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified a plethora risk loci. However, the variants/genes and underlying mechanisms not been extensively studied. Methods Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then into glutamatergic neurons (iGlut). Transcriptomic analysis functional iGlut co-cultured with mouse astrocytes assessed neuronal excitability lipid droplet formation. Results We putative causal SNP CLU that impacted accessibility transcription-factor(s), AD protective allele upregulating promoting neuron excitability. And, facilitated neuron-to-glia transfer astrocytic formation coupled reactive oxygen species (ROS) accumulation. These changes caused uptake less glutamate thereby altering Conclusions For strong AD-associated locus near Clusterin ( ), we connected an role through lipid-mediated neuron-glia communication. Our study provides insights how confers resilience interactions.

Language: Английский

Acetate enables metabolic fitness and cognitive performance during sleep disruption DOI

Qinqin He,

Liwei Ji,

Yanyan Wang

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(9), P. 1998 - 2014.e15

Published: Aug. 19, 2024

Language: Английский

Citations

17
The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4 DOI
Femke M. Feringa,

Sascha J. Koppes-den Hertog,

Lian Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 3, 2024

Abstract Lipid changes in the brain have been implicated many neurodegenerative diseases including Alzheimer’s Disease (AD), Parkinson’s disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named Neurolipid Atlas, that pre-populated with novel human, mouse isogenic induced pluripotent stem cell (iPSC)-derived lipidomics for different diseases. We show iPSC-derived neurons, microglia astrocytes display distinct lipid profiles recapitulate vivo lipotypes. Leveraging multiple datasets, AD risk gene ApoE4 drives cholesterol ester (CE) accumulation human recapitulating CE measured brain. Multi-omic interrogation of revealed plays major role astrocyte interferon-dependent pathways such as immunoproteasome histocompatibility complex (MHC) class I antigen presentation. through enhanced esterification suppresses immune activation astrocytes. Our commons, available at neurolipidatlas.com, provides user-friendly tool knowledge base better understanding dyshomeostasis

Language: Английский

Citations

9
Tau is required for glial lipid droplet formation and resistance to neuronal oxidative stress DOI
Lindsey D. Goodman, Isha Ralhan,

Xin Li

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(10), P. 1918 - 1933

Published: Aug. 26, 2024

Language: Английский

Citations

8
The circular RNA circbabo(5,6,7,8S) regulates lipid metabolism and neuronal integrity via TGF-β/ROS/JNK/SREBP signaling axis in Drosophila DOI Creative Commons
Jie Sheng, Xuemei Zhang, Weihong Liang

et al.

BMC Biology, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 5, 2025

Lipid droplets (LDs) are dynamic cytoplasmic lipid-storing organelles that play a pivotal role in maintaining cellular energy balance, lipid homeostasis, and metabolic signaling. Dysregulation of metabolism, particularly excessive lipogenesis, contributes to the abnormal accumulation LDs nervous system, which is associated with several neurodegenerative diseases. Circular RNAs (circRNAs) new class non-coding regulatory widely expressed eukaryotes. However, only subset has been functionally characterized. Here, we identified characterized circular RNA circbabo(5,6,7,8S) regulates lipogenesis neuronal integrity Drosophila melanogaster. derived from babo locus encodes type I receptor for transforming growth factor β (TGF-β). Depletion flies causes elevated droplet accumulation, progressive photoreceptor cell loss shortened lifespan, phenotypes rescued by restoring expression. In addition, RNA-seq epistasis analyses reveal these abnormalities caused aberrant activation SREBP signaling pathway. Furthermore, circbabo(5,6,7,8S)-depleted tissues display enhanced TGF-β pathway compromised mitochondrial function, resulting upregulation reactive oxygen species (ROS). Moreover, provide evidence protein circbabo(5,6,7,8S)-p, inhibits interfering assembly babo/put heterodimer complex. Lastly, show dysregulation ROS/JNK/SREBP cascade responsible LD neurodegeneration, lifespan elicited depletion. Our study demonstrates physiological protein-coding circRNA regulating metabolism integrity.

Language: Английский

Citations

1
Mitochondrial origins of the pressure to sleep DOI Creative Commons
Raffaele Sarnataro, Cecilia D. Velasco, Nicholas Monaco

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 25, 2024

Abstract To obtain a comprehensive, unbiased view of molecular changes in the brain that may underpin need for sleep, we have characterized transcriptomes single cells isolated from rested and sleep-deprived flies. Transcripts upregulated after sleep deprivation, sleep-control neurons projecting to dorsal fan-shaped body (dFBNs) but not ubiquitously brain, encode almost exclusively proteins with roles mitochondrial respiration ATP synthesis. These gene expression are accompanied by fragmentation, enhanced mitophagy, an increase number contacts between mitochondria endoplasmic reticulum, creating conduits replenishment peroxidized lipids. The morphological reversible recovery blunted installation electron overflow respiratory chain. Inducing or preventing fission fusion dFBNs alters electrical properties opposite directions: hyperfused increase, whereas fragmented decrease, neuronal excitability sleep. levels rise enforced waking because diminished consumption during arousal-mediated inhibition these neurons, which predisposes them heightened oxidative stress. Consistent this view, uncoupling flux synthesis relieves pressure while exacerbating mismatches supply demand (by powering light-driven proton pump) promotes Sleep, like ageing, be inescapable consequence aerobic metabolism.

Language: Английский

Citations

7
A fluorescent perilipin 2 knock-in mouse model reveals a high abundance of lipid droplets in the developing and adult brain DOI Creative Commons
Sofia Madsen, Ana C. Delgado, Christelle Cadilhac

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 28, 2024

Abstract Lipid droplets (LDs) are dynamic lipid storage organelles. They tightly linked to metabolism and can exert protective functions, making them important players in health disease. Most LD studies vivo rely on staining methods, providing only a snapshot. We therefore developed LD-reporter mouse by labelling the endogenous coat protein perilipin 2 (PLIN2) with tdTomato, enabling staining-free fluorescent visualisation living fixed tissues cells. Here we validate this model under standard high-fat diet conditions demonstrate that LDs highly abundant various cell types healthy brain, including neurons, astrocytes, ependymal cells, neural stem/progenitor cells microglia. Furthermore, also show during brain development be visualized using live imaging of embryonic slices. Taken together, our tdTom-Plin2 serves as novel tool study their dynamics both physiological diseased all expressing Plin2.

Language: Английский

Citations

7
An Engineered Cellular Carrier Delivers miR-138-5p to Enhance Mitophagy and Protect Hypoxic-Injured Neurons via the DNMT3A/Rhebl1 Axis DOI Creative Commons

Xingjia Zhu,

Qianqian Liu,

Fengwei Zhu

et al.

Acta Biomaterialia, Journal Year: 2024, Volume and Issue: 186, P. 424 - 438

Published: Aug. 8, 2024

Mitophagy influences the progression and prognosis of ischemic stroke (IS). However, whether DNA methylation in brain is associated with altered mitophagy hypoxia-injured neurons remains unclear. Here, miR-138–5p was found to be highly expressed exosomes secreted by astrocytes stimulated oxygen glucose deprivation/re-oxygenation (OGD/R), which could influence recovery OGD/R-injured through autophagy. Mechanistically, promotes stable expression Ras homolog enriched like 1(Rhebl1) DNA-methyltransferase-3a (DNMT3A), thereby enhancing ubiquitin-dependent maintain mitochondrial homeostasis. Furthermore, we employed glycosylation engineering bioorthogonal click reactions load mirna onto surface microglia deliver them injured region utilising inflammatory chemotactic properties achieve drug-targeted delivery central nervous system (CNS). Our findings demonstrate improves function miR-138–5p/DNMT3A/Rhebl1 axis. Additionally, our engineered cell vector-targeted promising for treating IS. In this study, demonstrated that under hypoxia plays a critical role treatment neurons. And find new target miR-138–5p, DNMT3A, affects neuronal thus exerts protective effect regulating Rbebl1. have developed carrier combining membrane utilized via intravenous injection. This groundbreaking study not only provides novel therapeutic approach ischemia-reperfusion but also establishes solid theoretical foundation further research on targeted drug diseases clinical applications.

Language: Английский

Citations

6
Glial lipid droplets resolve ROS during sleep DOI
Lindsey D. Goodman, Matthew J. Moulton, Hugo J. Bellen

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(4), P. 610 - 612

Published: Feb. 15, 2024

Language: Английский

Citations

4
Circadian coordination: understanding interplay between circadian clock and mitochondria DOI Creative Commons
Jeongah Kim, Woong Sun

Animal Cells and Systems, Journal Year: 2024, Volume and Issue: 28(1), P. 228 - 236

Published: May 7, 2024

Biological rhythms play a crucial role in temporally regulating behavioral, physiological, and cellular processes within our bodies. One prominent example is the circadian rhythm, which enables bodies to anticipate external cues regulate internal accordingly. The rhythm controlled by molecular feedback loop known as clock, present nearly all cells. regulation of genes involved mitochondrial function no exception. Key aspects such oxidative phosphorylation, biogenesis, morphology are regulated clock. Functional changes mitochondria can retrogradely affect rhythm. Furthermore, there also transcriptional clock-independent mitochondria. This review discusses independently or communication with clock nucleus at level.

Language: Английский

Citations

4
Glia: The Cellular Glue that binds Circadian Rhythms and Sleep DOI Creative Commons

Catarina Cavalhas-Almeida,

Amita Sehgal

SLEEP, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Glia are increasingly appreciated as serving an important function in the control of sleep and circadian rhythms. Glial cells Drosophila mammals regulate daily rhythms locomotor activity well homeostatic rebound following deprivation. In addition, they contribute to proposed functions sleep, with different mapping varied glial subtypes. Here, we discuss recent findings rodent models establishing a role glia or regulation synaptic plasticity, brain metabolism, removal cellular debris immune challenges. These underscore relevance for benefits attributed have implications understanding neurobiological mechanisms underlying associated disorders.

Language: Английский

Citations

0