scholarly journals Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A–C

2010 ◽  
Vol 189 (2) ◽  
pp. 223-232 ◽  
Author(s):  
Chieh Hsu ◽  
Yuichi Morohashi ◽  
Shin-ichiro Yoshimura ◽  
Natalia Manrique-Hoyos ◽  
SangYong Jung ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Rab Gtpase ◽  
Multivesicular Bodies ◽  
Dependent Manner ◽  
Intracellular Accumulation ◽  
Gtpase Activating Proteins ◽  
The Central Nervous System ◽  
And Function ◽  
Endosomal Vesicles ◽  
Activity Dependent

Oligodendrocytes secrete vesicles into the extracellular space, where they might play a role in neuron–glia communication. These exosomes are small vesicles with a diameter of 50–100 nm that are formed within multivesicular bodies and are released after fusion with the plasma membrane. The intracellular pathways that generate exosomes are poorly defined. Because Rab family guanosine triphosphatases (GTPases) together with their regulators are important membrane trafficking organizers, we investigated which Rab GTPase-activating proteins interfere with exosome release. We find that TBC1D10A–C regulate exosome secretion in a catalytic activity–dependent manner. We show that Rab35 is the target of TBC1D10A–C and that the inhibition of Rab35 function leads to intracellular accumulation of endosomal vesicles and impairs exosome secretion. Rab35 localizes to the surface of oligodendroglia in a GTP-dependent manner, where it increases the density of vesicles, suggesting a function in docking or tethering. These findings provide a basis for understanding the biogenesis and function of exosomes in the central nervous system.

scholarly journals Neurexin-Neuroligin Synaptic Complex Regulates Schizophrenia-Related DISC1/Kal-7/Rac1 “Signalosome”

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Sylwia Owczarek ◽  
Marie Louise Bang ◽  
Vladimir Berezin
Keyword(s):  
Central Nervous System ◽  
Cell Adhesion Molecules ◽  
Synaptic Membranes ◽  
Dependent Manner ◽  
Related Protein ◽  
Synaptic Complex ◽  
The Central Nervous System ◽  
And Function ◽  
Activity Dependent ◽  
The Brain

Neurexins (NXs) and neuroligins (NLs) are cell adhesion molecules that are localized at opposite sites of synaptic membranes. They interact with each other to promote the assembly, maintenance, and function of synapses in the central nervous system. Both NX and NL are cleaved from a membrane-attached intracellular domain in an activity-dependent manner, generating the soluble ectodomain of NX or NL. Expression of theNX1andNX3genes in the brain appears to be regulated by a schizophrenia-related protein, DISC1. Here, we show that soluble ecto-NX1βcan regulate the expression of DISC1 and induce signaling downstream of DISC1. We also show that NL1 binds to a well-characterized DISC1 interaction partner, Kal-7, and this interaction can be compromised by DISC1. Our results indicate that the NX/NL synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better understanding of the pathology of schizophrenia.

scholarly journals Functional dissection of Rab GTPases involved in primary cilium formation

2007 ◽  
Vol 178 (3) ◽  
pp. 363-369 ◽  
Author(s):  
Shin-ichiro Yoshimura ◽  
Johannes Egerer ◽  
Evelyn Fuchs ◽  
Alexander K. Haas ◽  
Francis A. Barr
Keyword(s):  
Membrane Trafficking ◽  
Primary Cilia ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Microtubule Cytoskeleton ◽  
Gtpase Activating Proteins ◽  
Cilia Formation ◽  
Sensory Structures ◽  
And Function ◽  
Specific Membrane

Primary cilia are sensory structures involved in morphogen signalling during development, liquid flow in the kidney, mechanosensation, sight, and smell (Badano, J.L., N. Mitsuma, P.L. Beales, and N. Katsanis. 2006. Annu. Rev. Genomics Hum. Genet. 7:125–148; Singla, V., and J.F. Reiter. 2006. Science. 313:629–633.). Mutations that affect primary cilia are responsible for several diseases, including neural tube defects, polycystic kidney disease, retinal degeneration, and cancers (Badano et al., 2006; Singla and Reiter, 2006). Primary cilia formation and function requires tight integration of the microtubule cytoskeleton with membrane trafficking (Singla and Reiter, 2006), and this is poorly understood. We show that the Rab GTPase membrane trafficking regulators Rab8a, -17, and -23, and their cognate GTPase-activating proteins (GAPs), XM_037557, TBC1D7, and EVI5like, are involved in primary cilia formation. However, other human Rabs and GAPs are not. Additionally, Rab8a specifically interacts with cenexin/ODF2, a basal body and microtubule binding protein required for cilium biogenesis (Ishikawa, H., A. Kubo, S. Tsukita, and S. Tsukita. 2005. Nat. Cell Biol. 7:517–524), and is the sole Rab enriched at primary cilia. These findings provide a basis for understanding how specific membrane trafficking pathways cooperate with the microtubule cytoskeleton to give rise to the primary cilia.

scholarly journals Evi5 promotes collective cell migration through its Rab-GAP activity

2012 ◽  
Vol 198 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Carl Laflamme ◽  
Gloria Assaker ◽  
Damien Ramel ◽  
Jonas F. Dorn ◽  
Desmond She ◽  
...  
Keyword(s):  
Cell Migration ◽  
Membrane Trafficking ◽  
Rab Gtpase ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Gtpase Activating Proteins ◽  
Guidance Receptors ◽  
Dependent Polarization ◽  
Drosophila Protein ◽  
Molecular Machinery

Membrane trafficking has well-defined roles during cell migration. However, its regulation is poorly characterized. In this paper, we describe the first screen for putative Rab–GTPase-activating proteins (GAPs) during collective cell migration of Drosophila melanogaster border cells (BCs), identify the uncharacterized Drosophila protein Evi5 as an essential membrane trafficking regulator, and describe the molecular mechanism by which Evi5 regulates BC migration. Evi5 requires its Rab-GAP activity to fulfill its functions during migration and acts as a GAP protein for Rab11. Both loss and gain of Evi5 function blocked BC migration by disrupting the Rab11-dependent polarization of active guidance receptors. Altogether, our findings deepen our understanding of the molecular machinery regulating endocytosis and subsequently cell signaling during migration.

Structure and function of ESCRT-III

2009 ◽  
Vol 37 (1) ◽  
pp. 156-160 ◽  
Author(s):  
Suman Lata ◽  
Guy Schoehn ◽  
Julianna Solomons ◽  
Ricardo Pires ◽  
Heinrich G. Göttlinger ◽  
...  
Keyword(s):  
Multivesicular Body ◽  
Multivesicular Bodies ◽  
Tubular Structures ◽  
Body Protein ◽  
Enveloped Viruses ◽  
Endosomal Sorting ◽  
Vacuolar Protein ◽  
And Function ◽  
Endosomal Vesicles

ESCRT-III (endosomal sorting complex required for transport III) is required for the formation and abscission of intraluminal endosomal vesicles, which gives rise to multivesicular bodies, budding of some enveloped viruses and cytokinesis. ESCRT-III is composed of 11 members in humans, which, except for one, correspond to the six ESCRT-III-like proteins in yeast. At least CHMP (charged multivesicular body protein) 2A and CHMP3 assemble into helical tubular structures that provide a platform for membrane interaction and VPS (vacuolar protein sorting) 4-catalysed effects leading to disassembly of ESCRT-III CHMP2A–CHMP3 polymers in vitro. Progress towards the understanding of the structures and function of ESCRT-III, its activation, its regulation by accessory factors and its role in abscission of membrane enveloped structures in concert with VPS4 are discussed.

scholarly journals Modulation of Synaptic Plasticity by Glutamatergic Gliotransmission: A Modeling Study

2016 ◽  
Vol 2016 ◽  
pp. 1-30 ◽  
Author(s):  
Maurizio De Pittà ◽  
Nicolas Brunel
Keyword(s):  
Synaptic Plasticity ◽  
Glutamate Release ◽  
Spike Timing ◽  
Biophysical Model ◽  
Dependent Manner ◽  
Inward Currents ◽  
Functional Relevance ◽  
And Function ◽  
Activity Dependent

Glutamatergic gliotransmission, that is, the release of glutamate from perisynaptic astrocyte processes in an activity-dependent manner, has emerged as a potentially crucial signaling pathway for regulation of synaptic plasticity, yet its modes of expression and function in vivo remain unclear. Here, we focus on two experimentally well-identified gliotransmitter pathways, (i) modulations of synaptic release and (ii) postsynaptic slow inward currents mediated by glutamate released from astrocytes, and investigate their possible functional relevance on synaptic plasticity in a biophysical model of an astrocyte-regulated synapse. Our model predicts that both pathways could profoundly affect both short- and long-term plasticity. In particular, activity-dependent glutamate release from astrocytes could dramatically change spike-timing-dependent plasticity, turning potentiation into depression (and vice versa) for the same induction protocol.

CD200-, CX3CL1-, and TREM2-mediated neuron-microglia interactions and their involvements in Alzheimer’s disease

2018 ◽  
Vol 29 (8) ◽  
pp. 837-848 ◽  
Author(s):  
Lihang Zhang ◽  
Juan Xu ◽  
Jinchao Gao ◽  
Yuncheng Wu ◽  
Ming Yin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Central Nervous System ◽  
Dependent Manner ◽  
Independent Manner ◽  
Physiological Conditions ◽  
The Central Nervous System ◽  
And Function ◽  
Cluster Of Differentiation ◽  
The Brain

Abstract Neurons and microglia are two major components in the central nervous system (CNS). The interactions between them play important roles in maintaining homeostasis of the brain. In recent years, substantial studies have focused on the interactions between neurons and microglia, revealing that microglia become reactive when the interactions are pathophysiologically interfered, usually accompanying neuronal injury, which is a common feature for Alzheimer’s disease (AD). Many molecules and factors participate in these physiological and pathological processes, either in a contact-dependent or a contact-independent manner. Accumulating studies have revealed that in the CNS, cluster of differentiation-200 (CD200) and fractalkine (CX3CL1) expressed mainly on neurons and triggering receptor expressed on myeloid cells 2 (TREM2) expressed mainly on microglia. These molecules can mediate neuron-microglia interactions in a contact-dependent manner and contribute to the pathogenesis of AD. Here, we review the expression, distribution, and function of CD200, CX3CL1, and TREM2 in regulating neuron-microglia interactions under physiological conditions as well as in AD.

scholarly journals Oligodendroglial Epigenetics, from Lineage Specification to Activity-Dependent Myelination

Life ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 62
Author(s):  
Mathilde Pruvost ◽  
Sarah Moyon
Keyword(s):  
Epigenetic Modifications ◽  
Environmental Cues ◽  
Oligodendrocyte Progenitor Cells ◽  
Lineage Specification ◽  
Cell Specification ◽  
Oligodendrocyte Progenitor ◽  
The Central Nervous System ◽  
And Function ◽  
Activity Dependent

Oligodendroglial cells are the myelinating cells of the central nervous system. While myelination is crucial to axonal activity and conduction, oligodendrocyte progenitor cells and oligodendrocytes have also been shown to be essential for neuronal support and metabolism. Thus, a tight regulation of oligodendroglial cell specification, proliferation, and myelination is required for correct neuronal connectivity and function. Here, we review the role of epigenetic modifications in oligodendroglial lineage cells. First, we briefly describe the epigenetic modalities of gene regulation, which are known to have a role in oligodendroglial cells. We then address how epigenetic enzymes and/or marks have been associated with oligodendrocyte progenitor specification, survival and proliferation, differentiation, and finally, myelination. We finally mention how environmental cues, in particular, neuronal signals, are translated into epigenetic modifications, which can directly influence oligodendroglial biology.

scholarly journals Membrane-Bound Meet Membraneless in Health and Disease

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1000 ◽  
Author(s):  
Chujun Zhang ◽  
Catherine Rabouille
Keyword(s):  
Phase Separation ◽  
Membrane Trafficking ◽  
Secretory Pathway ◽  
Dependent Manner ◽  
P Bodies ◽  
Early Secretory Pathway ◽  
Cell Organization ◽  
Health And Disease ◽  
Membrane Bound ◽  
And Function

Membraneless organelles (MLOs) are defined as cellular structures that are not sealed by a lipidic membrane and are shown to form by phase separation. They exist in both the nucleus and the cytoplasm that is also heavily populated by numerous membrane-bound organelles. Even though the name membraneless suggests that MLOs are free of membrane, both membrane and factors regulating membrane trafficking steps are emerging as important components of MLO formation and function. As a result, we name them biocondensates. In this review, we examine the relationships between biocondensates and membrane. First, inhibition of membrane trafficking in the early secretory pathway leads to the formation of biocondensates (P-bodies and Sec bodies). In the same vein, stress granules have a complex relationship with the cyto-nuclear transport machinery. Second, membrane contributes to the regulated formation of phase separation in the cells and we will present examples including clustering at the plasma membrane and at the synapse. Finally, the whole cell appears to transit from an interphase phase-separated state to a mitotic diffuse state in a DYRK3 dependent manner. This firmly establishes a crosstalk between the two types of cell organization that will need to be further explored.

scholarly journals Arf1 orchestrates Rab GTPase conversion at the trans-Golgi network

2021 ◽  
pp. mbc.E20-10-0664
Author(s):  
Laura L. Thomas ◽  
Carolyn M. Highland ◽  
J. Christopher Fromme
Keyword(s):  
Membrane Trafficking ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Membrane Domains ◽  
Trans Golgi Network ◽  
Important Regulator ◽  
And Function ◽  
Golgi Network ◽  
New Evidence

Rab family GTPases are key organizers of membrane trafficking and function as markers of organelle identity. Accordingly, Rab GTPases often occupy specific membrane domains and mechanisms exist to prevent the inappropriate mixing of distinct Rab domains. The yeast Golgi complex can be divided into two broad Rab domains: Ypt1 (Rab1) and Ypt6 (Rab6) are present at the early/medial Golgi and sharply transition to Ypt31/32 (Rab11) at the late Golgi/ trans-Golgi network (TGN). This Rab conversion has been attributed to GAP cascades in which Ypt31/32 recruits the Rab-GAPs Gyp1 and Gyp6 to inactivate Ypt1 and Ypt6, respectively. Here we report that Rab transition at the TGN involves additional layers of regulation. We provide new evidence confirming the TRAPPII complex as an important regulator of Ypt6 inactivation and uncover an unexpected role of the Arf1 GTPase in recruiting Gyp1 to drive Ypt1 inactivation at the TGN. Given its established role in directly recruiting TRAPPII to the TGN, Arf1 is therefore a master regulator of Rab conversion on maturing Golgi compartments.

scholarly journals ADrosophilamodel of neuronal ceroid lipofuscinosisCLN4reveals a hypermorphic gain of function mechanism

2019 ◽  
Author(s):  
Elliot Imler ◽  
Jin Sang Pyon ◽  
Selina Kindelay ◽  
Yong-quan Zhang ◽  
Sreeganga S. Chandra ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Gene Dosage ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Dependent Manner ◽  
Membrane Structures ◽  
Gain Of Function ◽  
Function Mechanism ◽  
Ubiquitinated Proteins ◽  
Activity Dependent ◽  
Dose Dependent

AbstractThe autosomal dominant neuronal ceroid lipofuscinoses (NCL)CLN4is caused by mutations in the synaptic vesicle (SV) protein CSPα, which is a critical co-chaperone of Hsc70 protecting synapses from activity-dependent degeneration. We developed the first animal models ofCLN4by expressing eitherCLN4mutant human CSPα (hCSPα) orDrosophilaCSP (dCSP) in fly neurons. Similar to patients,CLN4mutations induced excessive oligomerization of mutant hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, mostCLN4mutant hCSPα abnormally accumulated in axons and somata, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructurally, abnormal multi-laminar membrane structures were frequently observed in axons and somata next to degenerative abnormalities. The lethality, oligomerization and prelysosomal accumulation induced byCLN4mutations was attenuated by reducing wild type (WT) dCSP levels and enhanced by increasing WT dCSP or hCSPα levels, which indicates that bothCLN4alleles resemble dominant hypermorphic gain of function mutations. Furthermore, reducing the gene dosage of Hsc70 also attenuatedCLN4phenotypes. Taken together, we suggest thatCLN4alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.

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