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Journal of Parkinson's Disease 2021Recent data support an involvement of defects in homeostasis of phosphoinositides (PIPs) in the pathophysiology of Parkinson's disease (PD). Genetic mutations have been... (Review)
Review
Recent data support an involvement of defects in homeostasis of phosphoinositides (PIPs) in the pathophysiology of Parkinson's disease (PD). Genetic mutations have been identified in genes encoding for PIP-regulating and PIP-interacting proteins, that are associated with familial and sporadic PD. Many of these proteins are implicated in vesicular membrane trafficking, mechanisms that were recently highlighted for their close associations with PD. PIPs are phosphorylated forms of the membrane phospholipid, phosphatidylinositol. Their composition in the vesicle's membrane of origin, as well as membrane of destination, controls vesicular membrane trafficking. We review the converging evidence that points to the involvement of PIPs in PD. The review describes PD- and PIP-associated proteins implicated in clathrin-mediated endocytosis and autophagy, and highlights the involvement of α-synuclein in these mechanisms.
Topics: Autophagy; Endocytosis; Humans; Parkinson Disease; Phosphatidylinositols; alpha-Synuclein
PubMed: 34151859
DOI: 10.3233/JPD-212684 -
FEBS Letters Jun 2013The membrane of dense-core vesicles is present only in neural cells, where it is instrumental to the regulated discharge of important molecules such as the catecholamine... (Review)
Review
The membrane of dense-core vesicles is present only in neural cells, where it is instrumental to the regulated discharge of important molecules such as the catecholamine neurotransmitters. The mechanism underlying the specificity of this membrane to certain cell types has so far been unclear. Studies of this problem have been carried out by employing the pheochromocytoma PC12 cell line and its clones defective of dense-core vesicles. REST, the transcription repressor expressed at high levels in non-neural and at very low levels in neural cells, was found to regulate the genes encoding almost all the proteins of both the core and the membrane of the dense-core vesicles, including the transporter for catecholamines and the SNAREs for their exocytosis. Moreover, REST appears to control the assembly of the vesicle membrane. The role of REST in the various steps of the expression and function of the dense-core vesicle membrane is critical during development and participates in the dynamic regulation of mature cell physiology.
Topics: Animals; Catecholamines; Exocytosis; Gene Expression; Gene Expression Regulation; Humans; Intracellular Membranes; Protein Multimerization; Repressor Proteins; Secretory Vesicles
PubMed: 23651552
DOI: 10.1016/j.febslet.2013.04.024 -
Accounts of Chemical Research Jul 2019Extracellular vesicles are nanoparticles produced by cells. They are composed of cellular membrane with associated membrane proteins that surrounds an aqueous core...
Extracellular vesicles are nanoparticles produced by cells. They are composed of cellular membrane with associated membrane proteins that surrounds an aqueous core containing soluble molecules such as proteins and nucleic acids, like miRNA and mRNA. They are important in many physiological and pathological processes as they can transfer biological molecules from producer cells to acceptor cells. Preparation of the niche for cancer metastasis, stimulation of tissue regeneration and orchestration of the immune response are examples of the diverse processes in which extracellular vesicles have been implicated. As a result, these vesicles have formed a source of inspiration for many scientific fields. They could be used, for example, as liquid biopsies in diagnostics, as therapeutics in regenerative medicine, or as drug delivery vehicles for transport of medicines. In this Account, we focus on drug delivery applications. As we learn more and more about these vesicles, the complexity increases. What originally appeared to be a relatively uniform population of cellular vesicles is increasingly subdivided into different subsets. Cells make various distinct vesicle types whose physicochemical aspects and composition is influenced by parental cell type, cellular activation state, local microenvironment, biogenesis pathway, and intracellular cargo sorting routes. It has proven difficult to assess the effects of changes in production protocol on the characteristics of the cell-derived vesicle population. On top of that, each isolation method for vesicles necessarily enriches certain vesicle classes and subpopulations while depleting others. Also, each method is associated with a varying degree of vesicle purity and concomitant coisolation of nonvesicular material. What emerges is a staggering heterogeneity. This constitutes one of the main challenges of the field as small changes in production and isolation protocols may have large impact on the vesicle characteristics and on subsequent vesicle activity. We try to meet this challenge by careful experimental design and development of tools that enable robust readouts. By engineering the surface and cargo of extracellular vesicles through chemical and biological techniques, favorable characteristics can be enforced while unfavorable qualities can be overruled or masked. This is coupled to the precise evaluation of the interaction of extracellular vesicles with cells to determine the extracellular vesicle uptake routes and intracellular routing. Sensitive reporter assays enable reproducible analysis of functional delivery. This systematic evaluation and optimization of extracellular vesicles improves our insight into the critical determinants of extracellular vesicle activity and should improve translation into clinical application of engineered extracellular vesicles as a new class of drug delivery systems.
Topics: Animals; Antineoplastic Agents; Bioengineering; Drug Carriers; Drug Liberation; Extracellular Vesicles; Humans; Mice; Swine
PubMed: 31181910
DOI: 10.1021/acs.accounts.9b00109 -
Trends in Neurosciences Mar 2013Rapid information processing in our nervous system relies on high-frequency fusion of transmitter-filled vesicles at chemical synapses. Some sensory synapses possess... (Review)
Review
Rapid information processing in our nervous system relies on high-frequency fusion of transmitter-filled vesicles at chemical synapses. Some sensory synapses possess prominent electron-dense ribbon structures that provide a scaffold for tethering synaptic vesicles at the active zone (AZ), enabling sustained vesicular release. Here, we review functional data indicating that some central and neuromuscular synapses can also sustain vesicle-fusion rates that are comparable to those of ribbon-type sensory synapses. Comparison of the ultrastructure across these different types of synapses, together with recent work showing that cytomatrix proteins can tether vesicles and speed vesicle reloading, suggests that filamentous structures may play a key role in vesicle supply. We discuss potential mechanisms by which vesicle tethering could contribute to sustained high rates of vesicle fusion across ribbon-type, central, and neuromuscular synapses.
Topics: Action Potentials; Animals; Caenorhabditis elegans Proteins; Cell Communication; Cell Membrane; Cytoskeletal Proteins; Drosophila Proteins; Humans; Kinetics; Membrane Fusion; Microscopy, Electron; Nerve Tissue Proteins; Neuromuscular Junction; Neurons; Neurotransmitter Agents; SNARE Proteins; Species Specificity; Synaptic Transmission; Synaptic Vesicles
PubMed: 23164531
DOI: 10.1016/j.tins.2012.10.001 -
Proceedings of the National Academy of... Mar 2008Synaptic vesicles release neurotransmitter by following a process of vesicle docking and exocytosis. Although these steps are well established, it has been difficult to...
Synaptic vesicles release neurotransmitter by following a process of vesicle docking and exocytosis. Although these steps are well established, it has been difficult to observe and measure these rates directly in living synapses. Here, by combining the direct imaging of single synaptic vesicles and synaptic ribbons, I measure the properties of vesicle docking and evoked and spontaneous release from ribbon and extraribbon locations in a ribbon-type synaptic terminal, the goldfish retinal bipolar cell. In the absence of a stimulus, captured vesicles near ribbons associate tightly and only rarely undock or undergo spontaneous exocytosis. By contrast, vesicle capture at outlier sites is less stable and spontaneous exocytosis occurs at a higher rate. In response to a stimulus, exocytic events cluster near ribbons, but show no evidence of clustering away from ribbon sites. Together, the results here indicate that, although vesicles can associate and fuse both near and away from synaptic sites, vesicles at synaptic ribbons associate more stably and fusion is more tightly linked to stimuli.
Topics: Animals; Exocytosis; Goldfish; Membrane Fusion; Presynaptic Terminals; Retinal Bipolar Cells; Synaptic Vesicles
PubMed: 18339810
DOI: 10.1073/pnas.0709067105 -
Journal of Molecular Cell Biology Apr 2024Synaptic vesicles can undergo several modes of exocytosis, endocytosis, and trafficking within individual synapses, and their fates may be linked to different vesicular...
Synaptic vesicles can undergo several modes of exocytosis, endocytosis, and trafficking within individual synapses, and their fates may be linked to different vesicular protein compositions. Here, we mapped the intrasynaptic distribution of the synaptic vesicle proteins SV2B and SV2A in glutamatergic synapses of the hippocampus using three-dimensional electron microscopy. SV2B was almost completely absent from docked vesicles and a distinct cluster of vesicles found near the active zone. In contrast, SV2A was found in all domains of the synapse and was slightly enriched near the active zone. SV2B and SV2A were found on the membrane in the peri-active zone, suggesting the recycling from both clusters of vesicles. SV2B knockout mice displayed an increased seizure induction threshold only in a model employing high-frequency stimulation. Our data show that glutamatergic synapses generate molecularly distinct populations of synaptic vesicles and are able to maintain them at steep spatial gradients. The almost complete absence of SV2B from vesicles at the active zone of wildtype mice may explain why SV2A has been found more important for vesicle release.
Topics: Animals; Synaptic Vesicles; Nerve Tissue Proteins; Mice, Knockout; Membrane Glycoproteins; Hippocampus; Mice; Synapses; Seizures; Mice, Inbred C57BL
PubMed: 37682518
DOI: 10.1093/jmcb/mjad054 -
Journal of Neurochemistry May 2011SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptors)-mediated exocytotic release of neurotransmitters is a key process in neuronal... (Review)
Review
SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptors)-mediated exocytotic release of neurotransmitters is a key process in neuronal communication, controlled by a number of molecular interactions. A synaptic vesicle v-SNARE protein (VAMP2 or synaptobrevin), in association with two plasma membrane t-SNAREs (syntaxin 1 and SNAP25), assemble to form a protein complex that is largely accepted as the minimal membrane fusion machine. Acidification of the synaptic vesicle lumen by the large multi-subunit vacuolar proton pump (V-ATPase) is required for loading with neurotransmitters. Recent data demonstrate a direct interaction between the c-subunit of the V-ATPase and VAMP2 that appears to play a role at a late step in transmitter release. In this review, we examine evidence suggesting that the V0 membrane sector of the V-ATPase not only participates in proton pumping, but plays a second distinct role in neurosecretion, downstream of filling and close to vesicle fusion.
Topics: Animals; Humans; Membrane Fusion; Neurotransmitter Agents; Proton Pumps; SNARE Proteins; Synaptic Membranes; Synaptic Vesicles; Synaptosomal-Associated Protein 25; Syntaxin 1; Vacuolar Proton-Translocating ATPases; Vesicle-Associated Membrane Protein 2
PubMed: 21375531
DOI: 10.1111/j.1471-4159.2011.07234.x -
Multilamellar and Multivesicular Outer Membrane Vesicles Produced by a Buttiauxella agrestis Mutant.Applied and Environmental Microbiology Oct 2020Outer membrane vesicles (OMVs) are naturally released from Gram-negative bacteria and play important roles in various biological functions. Released vesicles are not...
Outer membrane vesicles (OMVs) are naturally released from Gram-negative bacteria and play important roles in various biological functions. Released vesicles are not uniform in shape, size, or characteristics, and little is known about this diversity of OMVs. Here, we show that deletion of , which encodes a part of the Tol-Pal system, leads to the production of multiple types of vesicles and increases overall vesicle production in the high-vesicle-forming type strain JCM 1090. The Δ mutant produced small OMVs and multilamellar/multivesicular OMVs (M-OMVs) as well as vesicles with a striking similarity to the wild type. M-OMVs, previously undescribed, contained triple-lamellar membrane vesicles and multiple vesicle-incorporating vesicles. Ultracentrifugation enabled the separation and purification of each type of OMV released from the Δ mutant, and visualization by quick-freeze deep-etch and replica electron microscopy indicated that M-OMVs are composed of several lamellar membranes. Visualization of intracellular compartments of Δ mutant cells showed that vesicles were accumulated in the broad periplasm, which is probably due to the low linkage between the outer and inner membranes attributed to the Tol-Pal defect. The outer membrane was invaginating inward by wrapping a vesicle, and the precursor of M-OMVs existed in the cell. Thus, we demonstrated a novel type of bacterial OMV and showed that unconventional processes enable the Δ mutant to form unique vesicles. Membrane vesicle (MV) formation has been recognized as a common mechanism in prokaryotes, and MVs play critical roles in intercellular interaction. However, a broad range of MV types and their multiple production processes make it difficult to gain a comprehensive understanding of MVs. In this work, using vesicle separation and electron microscopic analyses, we demonstrated that diverse types of outer membrane vesicles (OMVs) were released from an engineered strain, JCM 1090 Δ mutant. We also discovered a previously undiscovered type of vesicle, multilamellar/multivesicular outer membrane vesicles (M-OMVs), which were released by this mutant using unconventional processes. These findings have facilitated considerable progress in understanding MV diversity and expanding the utility of MVs in biotechnological applications.
Topics: Bacterial Proteins; Enterobacteriaceae; Mutation; Periplasmic Proteins
PubMed: 32801184
DOI: 10.1128/AEM.01131-20 -
Nanomaterials (Basel, Switzerland) Oct 2022The mechanical properties of vesicles were investigated as they were prepared, according to the ratio of mucin to dipalmitoylphosphatidylcholine (DPPC), using an atomic...
The mechanical properties of vesicles were investigated as they were prepared, according to the ratio of mucin to dipalmitoylphosphatidylcholine (DPPC), using an atomic force microscope (AFM). After the confirmation of the vesicle adsorption on a mica surface, an AFM-tip deflection, caused by the interaction between the tip and the vesicle, was measured. The deflection showed that the tip broke through into the vesicle twice. Each break meant a tip-penetration into the upper and lower portion of the vesicle. Only the first penetration allowed the Hertzian model available to estimate the vesicle mechanical moduli. Two moduli reduced as the ratio of mucin to DPPC increased to 0.5, but the moduli were little changed above the 0.5 ratio. These results seem to be a platform for the effect of the mucin on the plasma-membrane anchoring and cellular signaling.
PubMed: 36296873
DOI: 10.3390/nano12203683 -
Proceedings of the National Academy of... Jan 2007Coat protein I (COPI) vesicles arise from Golgi cisternae and mediate the recycling of proteins from the Golgi back to the endoplasmic reticulum (ER) and the transport...
Coat protein I (COPI) vesicles arise from Golgi cisternae and mediate the recycling of proteins from the Golgi back to the endoplasmic reticulum (ER) and the transport of Golgi resident proteins between cisternae. In vitro studies have produced evidence for two distinct types of COPI vesicles, but the in vivo sites of operation of these vesicles remain to be established. We have used a combination of electron tomography and immunolabeling techniques to examine Golgi stacks and associated vesicles in the cells of the scale-producing alga Scherffelia dubia and Arabidopsis preserved by high-pressure freezing/freeze-substitution methods. Five structurally distinct types of vesicles were distinguished. In Arabidopsis, COPI and COPII vesicle coat proteins as well as vesicle cargo molecules (mannosidase I and sialyltransferase-yellow fluorescent protein) were identified by immunogold labeling. In both organisms, the COPI-type vesicles were further characterized by a combination of six structural criteria: coat architecture, coat thickness, membrane structure, cargo staining, cisternal origin, and spatial distribution. Using this multiparameter structural approach, we can distinguish two types of COPI vesicles, COPIa and COPIb. COPIa vesicles bud exclusively from cis cisternae and occupy the space between cis cisternae and ER export sites, whereas the COPIb vesicles bud exclusively from medial- and trans-Golgi cisternae and are confined to the space around these latter cisternae. We conclude that COPIa vesicle-mediated recycling to the ER occurs only from cis cisternae, that retrograde transport of Golgi resident proteins by COPIb vesicles is limited to medial and trans cisternae, and that diffusion of periGolgi vesicles is restricted.
Topics: Arabidopsis; Biological Transport; COP-Coated Vesicles; Clathrin-Coated Vesicles; Endoplasmic Reticulum; Eukaryota; Golgi Apparatus
PubMed: 17185411
DOI: 10.1073/pnas.0609818104