Exosome-mediated release of bis(monoacylglycerol)phosphate is regulated by LRRK2 and Glucocerebrosidase activity DOI Creative Commons
Elsa Meneses‐Salas,

Marianna Arnold,

María Castellá

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 13, 2023

ABSTRACT The endo-lysosomal phospholipid, bis(monoacylglycerol)phosphate (BMP), is aberrantly elevated in the urine of Parkinson’s patients with mutations genes encoding leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GCase). Because BMP resides on regulates biogenesis intralumenal membranes that become extracellular vesicles (EVs) upon release, we hypothesized urinary may be driven by increased exocytosis BMP-enriched EVs. To test this hypothesis, analyzed metabolism EV-associated release wild type (WT) R1441G LRRK2-expressing mouse embryonic fibroblast (MEF) cells. Using immunofluorescence microscopy transmission electron detected structural alterations endo-lysosomes antibody-accessible pool, indicating mutant LRRK2 affects endolysosomal homeostasis. Biochemical analyses isolated EV fractions confirmed effect showing an increase LAMP2-positive EVs cells, which was partially restored inhibition but further augmented GCase inhibition. mass spectrometry, overall total di-22:6-BMP di-18:1-BMP cell lysates from MEFs compared to WT Inhibition cellular levels, whereas content. In decreased content tended it. metabolic labeling experiments, demonstrated not due synthesis, even though observed synthesizing enzyme, CLN5, patient-derived fibroblasts. Finally, pharmacological modulators associated secretion. Together, these results establish as a regulator levels cells its through EVs, activity modulating process Mechanistic insights studies have implications for potential use BMP-positive biomarker disease treatments.

Language: Английский

TMEM106B deficiency leads to alterations in lipid metabolism and obesity in the TDP-43Q331K knock-in mouse model DOI Creative Commons

Cha Yang,

Gwang Bin Lee, Ling Hao

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: Feb. 26, 2025

The TMEM106B gene, encoding a lysosomal membrane protein, is closely linked with brain aging and neurodegeneration. has been identified as risk factor for several neurodegenerative diseases characterized by aggregation of the RNA-binding protein TDP-43, including frontotemporal lobar degeneration (FTLD) limbic-predominant age-related TDP-43 encephalopathy (LATE). To investigate role in proteinopathy, we ablated TDP-43Q331K knock-in mouse line, which expresses an ALS-linked mutation at endogenous levels. We found that deficiency leads to glial activation, Purkinje cell loss, behavioral deficits mice without inducing typical pathology. Interestingly, ablation results significant body weight gain, increased fat deposition, hepatic triglyceride (TG) accumulation mice. In addition, lipidomic transcriptome analysis shows profound alteration lipid metabolism liver TDP-43Q331KTmem106b−/− Our studies reveal novel function provide new insights into their roles An unexpected obesity phenotype altered TMEM106B-deficient metabolism, providing

Language: Английский

Citations

1
Synthetic Lipid Biology DOI

Po-Hsun Brian Chen,

Xiangling Li, Jeremy M. Baskin

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Cells contain thousands of different lipids. Their rapid and redundant metabolism, dynamic movement, many interactions with other biomolecules have justly earned lipids a reputation as vexing class molecules to understand. Further, the cell's hydrophobic metabolites, assemble into supramolecular structures─most commonly bilayers, or membranes─from which they carry out myriad biological functions. Motivated by this daunting complexity, researchers across disciplines are bringing order seeming chaos membranes. Here, we formalize these efforts "synthetic lipid biology". Inspired idea, central synthetic biology, that our abilities understand build systems intimately connected, organize studies approaches numerous fields create, manipulate, analyze biomembranes. These include construction membranes from scratch using chemical chemoenzymatic synthesis, editing pre-existing optogenetics protein engineering, detection metabolism transport bioorthogonal chemistry, probing lipid–protein membrane biophysical properties. What emerges is portrait an incipient field where chemists, biologists, physicists, engineers work together in proximity─like themselves─to clearer description properties, behaviors, functions

Language: Английский

Citations

0
Mechanisms and functions of lysosomal lipid homeostasis DOI Creative Commons
Michael Ebner, Florian Fröhlich, Volker Haucke

et al.

Cell chemical biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
Isomerization of bis(monoacylglycero)phosphate by acyl migration DOI Creative Commons
Akira Abe, Vania Hinkovska‐Galcheva, Rakesh Kumar Verma

et al.

Journal of Lipid Research, Journal Year: 2025, Volume and Issue: unknown, P. 100789 - 100789

Published: March 1, 2025

Language: Английский

Citations

0
Fraternal twins at work: Structures of PLD3/4 reveal mechanism for lysosomal nucleic acid breakdown DOI
Oliver Daumke, Markus Daμμe

Structure, Journal Year: 2024, Volume and Issue: 32(6), P. 645 - 647

Published: June 1, 2024

Language: Английский

Citations

0
Molecular determinants of phospholipid treatment to reduce intracellular cholesterol accumulation in NPC1 deficiency DOI Creative Commons

Shikun Deng,

T Liu,

Olga Ilnytska

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(11), P. 107889 - 107889

Published: Oct. 11, 2024

Language: Английский

Citations

0
Lipid transfer at mitochondrial membrane contact sites DOI Creative Commons

Qingzhu Chu,

Wei-Ke Ji

Mitochondrial Communications, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Citations

0
Exosome-mediated release of bis(monoacylglycerol)phosphate is regulated by LRRK2 and Glucocerebrosidase activity DOI Creative Commons
Elsa Meneses‐Salas,

Marianna Arnold,

María Castellá

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 13, 2023

ABSTRACT The endo-lysosomal phospholipid, bis(monoacylglycerol)phosphate (BMP), is aberrantly elevated in the urine of Parkinson’s patients with mutations genes encoding leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GCase). Because BMP resides on regulates biogenesis intralumenal membranes that become extracellular vesicles (EVs) upon release, we hypothesized urinary may be driven by increased exocytosis BMP-enriched EVs. To test this hypothesis, analyzed metabolism EV-associated release wild type (WT) R1441G LRRK2-expressing mouse embryonic fibroblast (MEF) cells. Using immunofluorescence microscopy transmission electron detected structural alterations endo-lysosomes antibody-accessible pool, indicating mutant LRRK2 affects endolysosomal homeostasis. Biochemical analyses isolated EV fractions confirmed effect showing an increase LAMP2-positive EVs cells, which was partially restored inhibition but further augmented GCase inhibition. mass spectrometry, overall total di-22:6-BMP di-18:1-BMP cell lysates from MEFs compared to WT Inhibition cellular levels, whereas content. In decreased content tended it. metabolic labeling experiments, demonstrated not due synthesis, even though observed synthesizing enzyme, CLN5, patient-derived fibroblasts. Finally, pharmacological modulators associated secretion. Together, these results establish as a regulator levels cells its through EVs, activity modulating process Mechanistic insights studies have implications for potential use BMP-positive biomarker disease treatments.

Language: Английский

Citations

0