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

Lipid droplets and cellular lipid flux DOI

Alyssa J. Mathiowetz,

James A. Olzmann

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(3), P. 331 - 345

Published: March 1, 2024

Language: Английский

Citations

85
Making the connection: How membrane contact sites have changed our view of organelle biology DOI Creative Commons
Gia K. Voeltz, Eric M. Sawyer, György Hajnóczky

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(2), P. 257 - 270

Published: Jan. 1, 2024

The view of organelles and how they operate together has changed dramatically over the last two decades. textbook was that operated largely independently were connected by vesicular trafficking diffusion signals through cytoplasm. We now know all make functional close contacts with one another, often called membrane contact sites. study these sites moved to center stage in cell biology as it become clear play critical roles healthy developing cells during stress disease states. Contact have important intracellular signaling, lipid metabolism, motor-protein-mediated dynamics, organelle division, biogenesis. Here, we summarize major conceptual changes occurred come appreciate integrate activities organelles.

Language: Английский

Citations

58
The Role of ATG9 Vesicles in Autophagosome Biogenesis DOI Creative Commons
Elisabeth Holzer, Sascha Martens, Susanna Tulli

et al.

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(15), P. 168489 - 168489

Published: Feb. 10, 2024

Autophagy mediates the degradation and recycling of cellular material in lysosomal system. Dysfunctional autophagy is associated with a plethora diseases including uncontrolled infections, cancer neurodegeneration. In macroautophagy (hereafter autophagy) this encapsulated double membrane vesicles, autophagosomes, which form upon induction autophagy. The precursors to referred as phagophores, first appear small flattened cisternae, gradually enclose cargo they grow. assembly phagophores during initiation has been major subject investigation over past decades. A special focus ATG9, only conserved transmembrane protein among core machinery. majority ATG9 localizes Golgi-derived vesicles. Here we review recent advances breakthroughs regarding our understanding how vesicles it resides serve assemble machinery establish contact sites for autophagosome biogenesis. We also highlight open questions field that need be addressed years come.

Language: Английский

Citations

24
Multiple interactions mediate the localization of BLTP2 at ER-PM contacts to control plasma membrane dynamics DOI Creative Commons
Anbang Dai, Peng Xu, Chase Amos

et al.

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

Published: Feb. 8, 2025

Summary BLTP2/KIAA0100, a bridge-like lipid transfer protein, was reported to localize at contacts of the endoplasmic reticulum (ER) with either plasma membrane (PM) or recycling tubular endosomes depending on cell type. Our findings suggest that mediating bulk transport between ER and PM is key function this protein as BLTP2 tethers only after they become continuous it also macropinosomes in process fusing PM. We further identify interactions underlying binding PM, including phosphoinositides, adaptor proteins FAM102A FAM102B, N-BAR domain membrane-connected tubules. The absence results accumulation intracellular vacuoles, many which are connected membrane, pointing role control dynamics.

Language: Английский

Citations

2
LRRK2, lysosome damage, and Parkinson's disease DOI Creative Commons
Amanda Bentley‐DeSousa,

D.J. Clegg,

Shawn M. Ferguson

et al.

Current Opinion in Cell Biology, Journal Year: 2025, Volume and Issue: 93, P. 102482 - 102482

Published: Feb. 20, 2025

Limited understanding of regulatory mechanisms controlling LRRK2 kinase activity has hindered insights into both its normal biology and how dysregulation contributes to Parkinson's disease. Fortunately, recent years have yielded an increased is dynamically regulated by recruitment endolysosomal membranes. Notably, multiple small GTPases from the Rab family act as activators substrates LRRK2. Additionally, it was recently discovered that recruited to, activated at, stressed or damaged lysosomes through interaction with GABARAP via CASM (conjugation ATG8 single membranes) pathway. These discoveries position within rapidly growing field lysosomal damage repair mechanisms, offering important lysosome pathogenesis

Language: Английский

Citations

2
Insights from lipidomics into the terminal maturation of circulating human reticulocytes DOI Creative Commons
Giampaolo Minetti, Isabel Dorn, Harald Köfeler

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 27, 2025

Abstract In the age of “omics”, lipidomics erythropoiesis is still missing. How reticulocytes mature in circulation into functional erythrocytes also largely unknown. We have isolated here two populations human circulating at different levels maturation, and three subpopulations age, characterized evolution their lipidome. (Sphingomyelin+cholesterol) partly phosphatidylethanolamine increase relative to total lipids, whereas phosphatidylcholine phosphatidylserine decrease from immature erythrocytes, same time as surface area per cell decreases. The amounts more than 70 phospholipid subclasses, based on number carbon atoms (12–24) double bonds (0–6) fatty acids linked phospholipid, change process. As cannot perform de-novo synthesis, lipid remodeling likely requires selective removal phospholipids membrane or exchange with plasma both, possible involvement transfer proteins such VPS13A, which expressed erythrocytes. These findings not only shed light fundamental aspects red blood physiology but raise intriguing questions surrounding protein-lipid interactions, architecture, trafficking mechanisms.

Language: Английский

Citations

2
Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C DOI Open Access
Xinbo Wang, Peng Xu, Amanda Bentley‐DeSousa

et al.

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

Published: June 8, 2024

Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, bridge-like lipid transport protein and PD gene, sensor of stress/damage. Upon membrane perturbation, VPS13C rapidly relocates from the cytosol surface lysosomes where it tethers their membranes ER. This recruitment depends Rab7 requires signal at damaged releases an inhibited state which hinders access its VAB domain lysosome-bound Rab7. While another protein, LRRK2, also recruited stressed/damaged lysosomes, occurs much later stages by different mechanisms. Given VPS13 proteins bulk transport, these findings suggest delivery part early protective response damage.

Language: Английский

Citations

14
The bridge-like lipid transport protein VPS13C/PARK23 mediates ER–lysosome contacts following lysosome damage DOI Creative Commons

X.F. Wang,

Peng Xu, Amanda Bentley‐DeSousa

et al.

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

Published: April 10, 2025

Language: Английский

Citations

1
The Vps13-like protein BLTP2 is pro-survival and regulates phosphatidylethanolamine levels in the plasma membrane to maintain its fluidity and function DOI Creative Commons
Subhrajit Banerjee, Stephan Daetwyler, Xiaofei Bai

et al.

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

Published: Feb. 5, 2024

Lipid transport proteins (LTPs) facilitate nonvesicular lipid exchange between cellular compartments and have critical roles in homeostasis

Language: Английский

Citations

8
Quantitative imaging of species-specific lipid transport in mammalian cells DOI Creative Commons
Juan M. Iglesias‐Artola, Kai Schuhmann, Kristin Böhlig

et al.

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

Published: May 17, 2024

Abstract Eukaryotic cells produce over 1000 different lipid species which tune organelle membrane properties, control signalling and store energy 1,2 . How are selectively sorted between organelles to maintain specific identities is largely unknown due the difficulty image transport in 3 Here, we measured metabolism of individual mammalian using time-resolved fluorescence imaging bifunctional probes combination with ultra-high resolution mass spectrometry mathematical modelling. Quantification flux revealed that directional, non-vesicular responsible for fast, species-selective sorting compared slow, unspecific vesicular trafficking. Using genetic perturbations, found coupling active flipping passive a mechanism directional transport. Comparison metabolic conversion rates showed dominates distribution lipids while species-specific phospholipid controls neutral accumulation. Our results provide first quantitative map retrograde 4 We anticipate our pipeline mapping through physical chemical space will boost understanding cell biology disease.

Language: Английский

Citations

7