Altered lipid profile and reduced neuronal support in human induced pluripotent stem cell‐derived astrocytes from adrenoleukodystrophy patients DOI Creative Commons
Roberto Montoro Ferrer, Yorrick R. J. Jaspers,

Inge M. E. Dijkstra

et al.

Journal of Inherited Metabolic Disease, Journal Year: 2024, Volume and Issue: 48(1)

Published: Dec. 20, 2024

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder resulting from pathogenic variants in the ABCD1 gene that primarily affects nervous system and characterized by progressive axonal degeneration spinal cord peripheral nerves leukodystrophy. Dysfunction of very long-chain fatty acid (VLCFA) degradation has been implicated ALD pathology, but impact on astrocytes, which critically support neuronal function, remains poorly understood. Fibroblasts four patients were reprogrammed to generate human-induced pluripotent stem cells (hiPSC). hiPSC-derived astrocytes generated study astrocytic homeostasis. Our reveals significant changes lipidome an enrichment VLCFAs across multiple lipid classes, including triacylglycerols, cholesteryl esters, phosphatidylcholines. Importantly, not only exhibit intrinsic dysregulation also affect dendritic tree complexity neurons co-culture systems. These findings highlight cell-autonomous effects protein their microenvironment, shed light potential mechanisms underlying neuropathology, underscore critical role health.

Language: Английский

The ELOVL proteins: Very and ultra long-chain fatty acids at the crossroads between metabolic and neurodegenerative disorders DOI Creative Commons
Enza Ferrero, Frédéric M. Vaz, David Cheillan

et al.

Molecular Genetics and Metabolism, Journal Year: 2025, Volume and Issue: 144(3), P. 109050 - 109050

Published: Feb. 4, 2025

Language: Английский

Citations

1
Identification of the growth cone as a probe and driver of neuronal migration in the injured brain DOI Creative Commons
Chikako Nakajima, Masato Sawada,

Erika Umeda

et al.

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

Published: March 9, 2024

Abstract Axonal growth cones mediate axonal guidance and regulation. We show that migrating neurons in mice possess a cone at the tip of their leading process, similar to axons, terms cytoskeletal dynamics functional responsivity through protein tyrosine phosphatase receptor type sigma (PTPσ). Migrating-neuron respond chondroitin sulfate (CS) PTPσ collapse, which leads inhibition neuronal migration. In presence CS, can revert extended morphology when filopodia interact with heparan (HS), thus re-enabling Implantation an HS-containing biomaterial CS-rich injured cortex promotes extension improve migration regeneration neurons, thereby enabling recovery. Thus, is responsive extracellular environments acts as primary regulator

Language: Английский

Citations

8
Lipid Rafts: The Maestros of Normal Brain Development DOI Creative Commons

Barbara Viljetić,

Senka Blažetić, Irena Labak

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(3), P. 362 - 362

Published: March 18, 2024

Lipid rafts, specialised microdomains within cell membranes, play a central role in orchestrating various aspects of neurodevelopment, ranging from neural differentiation to the formation functional neuronal networks. This review focuses on multifaceted involvement lipid rafts key neurodevelopmental processes, including differentiation, synaptogenesis and myelination. Through spatial organisation signalling components, facilitate precise events that determine fate during embryonic development adulthood. The evolutionary conservation underscores their fundamental importance for structural complexity nervous system all species. Furthermore, there is increasing evidence environmental factors can modulate composition function influence processes. Understanding intricate interplay between neurodevelopment not only sheds light mechanisms governing brain but also has implications therapeutic strategies aimed at cultivating networks addressing disorders.

Language: Английский

Citations

7
Catalytic mechanism of trans-2-enoyl-CoA reductases in the fatty acid elongation cycle and its cooperative action with fatty acid elongases DOI Creative Commons

Ryoya Kato,

Yuka Takenaka,

Yusuke Ohno

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(2), P. 105656 - 105656

Published: Jan. 15, 2024

The fatty acid (FA) elongation cycle produces very-long-chain FAs with ≥C21, which have unique physiological functions. Trans-2-enoyl-CoA reductases (yeast, Tsc13; mammals, TECR) catalyze the reduction reactions in fourth step of FA and sphingosine degradation pathway. However, their catalytic residues coordinated action complex are unknown. To reveal these, we generated analyzed Ala-substituted mutants 15 Tsc13. An vitro assay showed that nine these were less active than WT protein, E91A Y256A being least active. Growth complementation analysis, measurement ceramide levels, deuterium-sphingosine labeling revealed function mutant was substantially impaired vivo. In addition, found activity elongases, first cycle, reduced absence Similar results observed Tsc13 E91A-expressing cells, is attributable to interaction between elongases Elo2/Elo3. Finally, E94A Y248A human TECR, correspond Tsc13, almost no activity, respectively. Based on predicted three-dimensional structure speculate Tyr256/Tyr248 Tsc13/TECR residue supplies a proton trans-2-enoyl-CoAs. Our findings provide clue concerning mechanism complex.

Language: Английский

Citations

3
Targeting ABCD1-ACOX1-MET/IGF1R axis suppresses multiple myeloma DOI
Zhannan Han, Zhibo Yan,

Zhehan Ma

et al.

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

Published: Jan. 30, 2025

Language: Английский

Citations

0
A clinical drug candidate that triggers non-apoptotic cancer cell death DOI Creative Commons
Scott J. Dixon, Logan B. Leak, Ziwei Wang

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 11, 2025

Small molecules that induce non-apoptotic cell death are of fundamental mechanistic interest and may be useful to treat certain cancers. Here, we report tegavivint, a drug candidate undergoing human clinical trials, can activate unique mechanism in sarcomas other cancer cells. This lethal is distinct from ferroptosis, necroptosis pyroptosis requires the lipid metabolic enzyme trans -2,3-enoyl-CoA reductase (TECR). TECR canonically involved synthesis very long chain fatty acids but appears promote response CIL56 tegavivint via saturated long-chain acid palmitate. These findings outline lipid-dependent induced by currently being tested humans.

Language: Английский

Citations

0
Extracellular vesicular delivery of ceramides from pulmonary macrophages to endothelial cells facilitates chronic obstructive pulmonary disease DOI Creative Commons
Qiqing Huang,

Tutu Kang,

Shaoran Shen

et al.

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 7, 2025

Ceramides are known for their harmful, cell-autonomous effects in cigarette smoke (CS)-triggered chronic obstructive pulmonary disease (COPD), yet potential role as intercellular signals COPD pathogenesis remains unclear. This study aims to investigate whether ceramides act cell-nonautonomous mediators of development by transmitting metabolic stress from macrophages endothelial cells (ECs), compromising function and thereby orchestrating the inflammation. We analyzed single-cell RNA sequencing data human lung tissues bulk alveolar (AMs) patients transcriptomic profiles ceramide biosynthesis enzymes. The expression changes several key enzymes were validated sections, AMs isolated CS-exposed mice, extract (CSE)-treated macrophages. Ceramide levels extracellular vesicles (EVs) quantified using mass spectroscopy lipidomics. EVs further characterized transmission electron microscopy nanoparticle tracking analysis. uptake macrophage-derived ECs on barriers evaluated vitro a co-culture system vivo mouse model. CS exposure upregulated involved de novo macrophages, increasing long- very long-chain ceramides. These packaged into delivered ECs, where they disrupted gap junctions, increased permeability, impaired EC migration. Silencing these could block this communication between mediated EV-delivered ceramides, protecting exposure. When intratracheally administered ceramide-rich exacerbated facilitating barrier disruption. Our uncovered novel mechanism pathogenesis, propagate CS-induced via ceramide-laden EVs, leading dysfunction. pathway represents target therapeutic intervention COPD. Chronic (COPD) is condition caused damage airways or other parts often triggered smoking. triggers inflammation that airflow make breathing difficult. While we know type fat molecule, can harm inside lungs, it was unclear how might affect different body. In study, explored move contribute found increases production immune called then tiny particles released which travel cells, especially lining blood vessels (endothelial cells). Upon entering disrupt making lung's more leaky damaging ability repair. process worsens suggests be new treating blocking harmful cells.

Language: Английский

Citations

0
Hidden β-γ Dehydrogenation Products in Long-Chain Fatty Acid Oxidation Unveiled by NMR: Implications on Lipid Metabolism DOI Creative Commons
Simone Fabbian,

Beatrice Masciovecchio,

Elisabetta Schievano

et al.

ACS Bio & Med Chem Au, Journal Year: 2025, Volume and Issue: 5(2), P. 262 - 267

Published: March 15, 2025

We present a comprehensive analysis of the initial α,β-dehydrogenation step in long-chain fatty acid β-oxidation (FAO). focused on palmitoyl-CoA oxidized by two mitochondrial acyl-CoA dehydrogenases, very-long-chain dehydrogenase (VLCAD) and family member 9 (ACAD9), both implicated diseases. By combining MS NMR, we identified (2E)-hexadecenoyl-CoA as expected α-β-dehydrogenation product also E Z stereoisomers 3-hexadecenoyl-CoA: "γ-oxidation" product. This finding reveals an alternative catalytic pathway FAO, suggesting potential regulatory role for ACAD9 VLCAD during metabolism.

Language: Английский

Citations

0
Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy DOI Open Access
Pierre Bougnères, Catherine Le Stunff

Genes, Journal Year: 2025, Volume and Issue: 16(5), P. 590 - 590

Published: May 17, 2025

Background: X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, same mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting middle-aged adults. The accumulation undegraded VLCFA glial cell membranes and myelin has long been thought to be central mechanism X-ALD. Methods: This review discusses studies mouse drosophila models that have modified our views pathogenesis. Results: In Abcd1 knockout (KO) mimics disease, late manifestations are rapidly reversed transfer oligodendrocytes (OLs). peroxin-5 KO model, selective impairment peroxisomal biogenesis OLs achieves an almost perfect phenocopy cerebral ALD. A model revealed myelinating cells production toxic lipid able poison axons activate cells. Other showed critical role providing energy substrates axons. addition, on microglial changing substates improved understanding neuroinflammation. Conclusions: Animal supporting primary axonal pathology secondary microglia allow us revisit mechanisms. Beyond mutations, pathogenesis depends unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, stochasticity crosstalk between multiple types among billions neurons.

Language: Английский

Citations

0
Tegavivint triggers TECR-dependent nonapoptotic cancer cell death DOI
Logan B. Leak, Ziwei Wang, Alby J. Joseph

et al.

Nature Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: May 26, 2025

Language: Английский

Citations

0