Neurodegenerative and Neurodevelopmental Roles for Bulk Lipid Transporters VPS13A and BLTP2 DOI Creative Commons
Sarah D. Neuman, Rajan Thakur, Scott J. Gratz

et al.

Movement Disorders, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

Abstract Background Bridge‐like lipid transfer proteins (BLTPs) mediate bulk transport at membrane contact sites. Mutations in BLTPs are linked to both early‐onset neurodevelopmental and later‐onset neurodegenerative diseases, including movement disorders. The tissue specificity temporal requirements of disease pathogenesis remain poorly understood. Objective objective this study was determine tissue‐specific aging‐dependent roles for VPS13A BLTP2 using Drosophila models. Methods We generated knockdowns the ortholog ( Vps13 ) hobbit neurons muscles . analyzed age‐dependent locomotor behavior, neurodegeneration, synapse development function. Results Neuron‐specific loss caused neurodegeneration followed by deficits reduced lifespan, whereas muscle‐specific affected only lifespan. In contrast, neuronal resulted severe defects without muscle impaired synaptogenesis neurotransmission neuromuscular junction. Conclusions maintains survival, orchestrates synaptic development. phenotypic BLTP function provides mechanistic insights into distinct trajectories BLTP‐associated © 2025 Author(s). Movement Disorders published Wiley Periodicals LLC on behalf International Parkinson Disorder Society.

Language: Английский

Oxidative stress in diabetes mellitus and its complications: From pathophysiology to therapeutic strategies DOI Creative Commons
Xingyu Chen, Na Xie,

Lixiang Feng

et al.

Chinese Medical Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 8, 2024

Oxidative stress due to aberrant metabolism is considered as a crucial contributor diabetes and its complications. Hyperglycemia hyperlipemia boost excessive reactive oxygen species generation by elevated mitochondrial respiration, increased nicotinamide adenine dinucleotide phosphate oxidase activity, enhanced pro-oxidative processes, including protein kinase C pathways, hexosamine, polyol, advanced glycation endproducts, which exacerbate oxidative stress. plays significant role in the onset of associated complications impairing insulin production, increasing resistance, maintaining hyperglycemic memory, inducing systemic inflammation. A more profound comprehension molecular processes that link new preventive therapeutic strategies. Therefore, this review discusses mechanisms underlying how contributes mellitus We also summarize current approaches for prevention treatment targeting pathways diabetes.

Language: Английский

Citations

7
A conserved megaprotein-based molecular bridge critical for lipid trafficking and cold resilience DOI Creative Commons

Changnan Wang,

Bingying Wang, Taruna Pandey

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 10, 2022

Cells adapt to cold by increasing levels of unsaturated phospholipids and membrane fluidity through conserved homeostatic mechanisms. Here we report an exceptionally large evolutionarily protein LPD-3 in C. elegans that mediates lipid trafficking confer resilience. We identify lpd-3 mutants a mutagenesis screen for genetic suppressors the desaturase FAT-7. bridges endoplasmic reticulum (ER) plasma membranes (PM), forming structurally predicted hydrophobic tunnel trafficking. exhibit abnormal phospholipid distribution, diminished FAT-7 abundance, organismic vulnerability cold, are rescued Lecithin comprising phospholipids. Deficient homologues Zebrafish mammalian cells cause defects similar those observed elegans. As mutations BLTP1, human orthologue lpd-3, Alkuraya-Kucinskas syndrome, family proteins may serve as highway critical ER-associated non-vesicular resilience stress eukaryotic cells.

Language: Английский

Citations

23
Bridge-like lipid transfer protein family member 2 suppresses ciliogenesis DOI
Jan Parolek, Christopher G. Burd

Molecular Biology of the Cell, Journal Year: 2024, Volume and Issue: 35(5)

Published: March 27, 2024

Bridge-like lipid transfer protein family member 2 (BLTP2) is an evolutionary conserved with unknown function(s). The absence of BLTP2 in Drosophila melanogaster results impaired cellular secretion and larval death, while mice ( Mus musculus), it causes preweaning lethality. Structural predictions propose that belongs to the repeating β-groove domain-containing (also called VPS13) family, forming a long tube hydrophobic core, suggesting operates as (LTP). We establish negative regulator ciliogenesis RPE-1 cells based on strong genetic interaction WDR44, gene also suppresses ciliogenesis. Like localizes membrane contact sites involving endoplasmic reticulum tubular endosome network HeLa depletion enhanced grown serum-containing medium, condition where normally suppressed. This study establishes human putative LTP acting between endosomes ER regulates primary cilium biogenesis.

Language: Английский

Citations

5
Structural basis of bulk lipid transfer by bridge-like lipid transfer protein LPD-3 DOI Open Access
Yunsik Kang, Katherine S. Lehmann, Juan M. Vanegas

et al.

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

Published: June 22, 2024

Abstract Bridge-like lipid transport proteins (BLTPs) are an evolutionarily conserved family of that localize to membrane contact sites and thought mediate the bulk transfer lipids from a donor membrane, typically endoplasmic reticulum (ER), acceptor such as cell or organelle 1 . Despite fundamental importance BLTPs for cellular function, architecture, composition, mechanisms remain poorly characterized. Here, we present subunit composition cryo-electron microscopy structure native LPD-3 BLTP complex isolated transgenic C. elegans folds into elongated, rod-shaped tunnel whose interior is filled with ordered molecules coordinated by track ionizable residues line one side tunnel. forms two previously uncharacterized proteins, here named “Intake” “Spigot”, both which interact N-terminal end where enter Intake has three transmembrane helices, borders entrance tunnel; Spigot helix extends 80 Å along cytosolic surface LPD-3. Experiments in multiple model systems indicate plays role ER-PM site formation. Our structural data, together molecular dynamics simulations region bilayer, reveal protein-lipid interactions suggest how LPD-3-complex mediates provide foundation mechanistic studies BLTPs.

Language: Английский

Citations

5
Imaging Interorganelle Phospholipid Transport by Extended Synaptotagmins Using Bioorthogonally Tagged Lipids DOI
Lin Luan, Dongjun Liang, Din-Chi Chiu

et al.

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(8), P. 1683 - 1694

Published: July 18, 2024

The proper distribution of lipids within organelle membranes requires rapid interorganelle lipid transport, much which occurs at membrane contact sites and is mediated by transfer proteins (LTPs). Our current understanding LTP mechanism function based largely on structural studies in vitro reconstitution. Existing cellular assays for use indirect readouts, it remains an open question as to whether substrate specificity transport kinetics established are similar settings. Here, we harness bioorthogonal chemistry develop tools direct visualization phospholipids between the plasma (PM) endoplasmic reticulum (ER). Unnatural fluorescent phospholipid analogs generated transphosphatidylation activity phospholipase D (PLD) PM rapidly transported ER dependent part upon extended synaptotagmins (E-Syts), a family LTPs ER-PM sites. Ectopic expression artificial E-Syt-based tether ER-mitochondria results accumulation mitochondria. Finally, reconstitution demonstrate that bona fide E-Syt substrates. Thus, situ via PLD chemical tagging can enable mediate bulk

Language: Английский

Citations

5
Genome-wide CRISPR screen reveals CLPTM1L as a lipid scramblase required for efficient glycosylphosphatidylinositol biosynthesis DOI Creative Commons
Yicheng Wang, Anant K. Menon, Yuta Maki

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(14)

Published: March 28, 2022

SignificanceScramblases translocate lipids across the lipid bilayer without consumption of ATP, thereby regulating distributions in cellular membranes. Cytosol-to-lumen translocation endoplasmic reticulum (ER) membrane is a common process among glycoconjugates involved posttranslational protein modifications eukaryotes. These translocations are thought to be mediated by specific ER-resident scramblases, but identity these proteins and underlying molecular mechanisms have been elusive. Here, we show that CLPTM1L, an integral with eight putative transmembrane domains, major scramblase efficient glycosylphosphatidylinositol biosynthesis ER membrane. Our results validate long-standing hypothesis scramblases ensure for glycosylation pathways.

Language: Английский

Citations

21
The bridge-like lipid transfer protein (BLTP) gene group: introducing new nomenclature based on structural homology indicating shared function DOI Creative Commons
Bryony Braschi, Elspeth A. Bruford,

Amy T. Cavanagh

et al.

Human Genomics, Journal Year: 2022, Volume and Issue: 16(1)

Published: Dec. 2, 2022

The HUGO Gene Nomenclature Committee assigns unique symbols and names to human genes. use of approved nomenclature enables effective communication between researchers, there are multiple examples how the usage unapproved alias can lead confusion. We discuss here a recent update (May 2022) for set genes that encode proteins with shared repeating β-groove domain. Some encoded by in this group have already been shown function as lipid transporters. By working researchers field, we able introduce new root symbol (BLTP, which stands "bridge-like transfer protein") domain-based gene group. This not only reflects domain these proteins, but also takes into consideration mounting evidence transport function.

Language: Английский

Citations

20
The Endoplasmic Reticulum and Its Contacts: Emerging Roles in Axon Development, Neurotransmission, and Degeneration DOI Creative Commons
Marijn Kuijpers, Phuong The Nguyen, Volker Haucke

et al.

The Neuroscientist, Journal Year: 2023, Volume and Issue: 30(5), P. 545 - 559

Published: March 24, 2023

The neuronal endoplasmic reticulum (ER) consists of a dynamic, tubular network that extends all the way from soma into dendrites, axons, and synapses. This morphology gives rise to an enormous membrane surface area that, through presence tethering proteins, lipid transfer ion channels, plays critical roles in local calcium regulation, dynamics, supply ions lipids other organelles. Here, we summarize recent advances highlight various ER axonal growth, repair, presynaptic function. We review variety contact sites between organelles describe their influence on neurodevelopment neurotransmission.

Language: Английский

Citations

13
The (social) lives, deaths, and biophysical phases of lipid droplets DOI Creative Commons
W. Mike Henne

Current Opinion in Cell Biology, Journal Year: 2023, Volume and Issue: 82, P. 102178 - 102178

Published: June 1, 2023

Language: Английский

Citations

12
The role of lipid scramblases in regulating lipid distributions at cellular membranes DOI
Yicheng Wang, Taroh Kinoshita

Biochemical Society Transactions, Journal Year: 2023, Volume and Issue: 51(5), P. 1857 - 1869

Published: Sept. 28, 2023

Glycerophospholipids, sphingolipids and cholesterol assemble into lipid bilayers that form the scaffold of cellular membranes, in which proteins are embedded. Membrane composition membrane protein profiles differ between plasma intracellular membranes two leaflets a membrane. Lipid distributions mediated by translocases, including flippases scramblases. Flippases use ATP to catalyze inward movement specific lipids leaflets. In contrast, bidirectional flip-flop movements across scramblases an ATP-independent manner. Scramblases have been implicated disrupting asymmetry membrane, glycosylation, autophagosome biogenesis, lipoprotein secretion, droplet formation communications organelles. Although were identified over 10 years ago, most progress about localized has made last few years. Herein, we review role regulating focusing primarily on membrane-localized

Language: Английский

Citations

11