Regulation Of Biosynthetic Cargo Trafficking In Neurons
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Regulation Of Biosynthetic Cargo Trafficking In Neurons
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Author : Iryna Pustova
language : en
Publisher:
Release Date : 2023
Regulation Of Biosynthetic Cargo Trafficking In Neurons written by Iryna Pustova and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2023 with categories.
Neurons are highly polarized cells with extremely long projections: dendrites and axons (together referred to as neurites). The central secretory dogma states that all protein synthesis and early secretory events take place in the cell body of a neuron, the soma. Yet, computational studies fail to reconcile experimental evidence with this notion proposing that there must be local protein synthesis and trafficking routes in distal neurites to support the function of a neuronal cell (reviewed in Chapter 1). Indeed, multiple lines of evidence from transcriptomics and protein translation studies indicate that local protein synthesis takes place independently of the soma. Amongst locally translated proteins, there are numerous secreted and membrane proteins. Yet, it is not clear how these newly synthesized proteins can be secreted locally, mainly, because the secretory pathway is largely understudied, especially in human neurons. Thus, I used human-induced pluripotent stem cells that I differentiated into cortical neurons to study the secretory pathway in distal neurites. In Chapter 2, I show that the secretory events occur in distal neuronal projections independently of the cell body. In fact, I find that nascent proteins are trafficked using an unconventional pathway via recycling endosomes. In addition, I uncover surprising new roles for TFG, a ubiquitously expressed protein and an important player in the early secretory pathway. Missense mutations in TFG have been identified in patients with neurodegenerative disorders though it is not clear how TFG results in disease. In Chapter 2, I show that TFG is not only important in the early secretory events in the conventional ER-to-Golgi trafficking, but it also mediates the unconventional secretory route where newly synthesized proteins exit ER and enter endosomes locally in distal neurites. Curiously, I find that TFG abundantly localizes with endosomes, suggesting that it must have an additional role in the endosomal pathway. Thus, I find that TFG has three distinct roles in neuronal cells: 1) conventional ER-to-Golgi trafficking in the soma, 2) unconventional ER-to-endosome route in distal neurites, 3) regulation of endosomal pathway. Future work, discussed in Chapter 3, will shed light on how TFG regulates the latter and how mutations in TFG lead to neurodegeneration.
Local Biosynthetic Trafficking Of Synaptic Proteins In Neuronal Dendrites
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Author : Aaron Benjamin Bowen
language : en
Publisher:
Release Date : 2017
Local Biosynthetic Trafficking Of Synaptic Proteins In Neuronal Dendrites written by Aaron Benjamin Bowen and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2017 with categories.
Neurons face the challenge of regulating the abundance, distribution and repertoire of integral membrane proteins on the surface of their immense, architecturally complex dendritic arbors. While the endoplasmic reticulum (ER) supports local translation of secretory cargo in all dendrites, most dendrites lack the Golgi apparatus (GA), an essential organelle for conventional secretory trafficking. Thus, whether secretory cargo is locally trafficked in dendrites through a non-canonical pathway remains a fundamental question. We have defined the trafficking itinerary for key synaptic molecules in dendrites. Following ER exit, the AMPA-type glutamate receptor GluA1 and neuroligin 1 undergo spatially restricted entry into the dendritic secretory pathway and accumulate in recycling endosomes (REs) located in dendrites and spines prior to reaching the plasma membrane. Surprisingly, surface delivery of GluA1 occurred even when GA function was disrupted. Thus, in addition to their canonical role in protein recycling, REs are critical mediators of forward secretory trafficking in neuronal dendrites and spines through a specialized GA-independent trafficking network. While the SNARE machinery that supports biosynthetic trafficking from the GA to the plasma membrane in neurons is not known, the SNAREs that mediate RE exocytosis have been partially defined. Surprisingly, we found that constitutive trafficking of GluA1 through REs does not depend on VAMP2, an R-SNARE with a well-defined role in RE exocytosis. Instead, the clostridial-neurotoxin insensitive SNARE VAMP7 defined a pool of GluA1-containing transport vesicles and was required for their delivery to the plasma membrane. Synaptic stimulation accelerated the delivery of GluA1 from this pool. Interestingly, while this activity-regulated delivery required VAMP2, inhibition of VAMP7 had no effect on activity-induced exocytosis. Thus, VAMP2 and VAMP7 play complementary roles in activity-induced and constitutive delivery of new synaptic proteins. Overall we have identified a novel biosynthetic pathway that involves GA-independent transfer of cargoes to the dendritic RE compartment. Subsequent exocytosis of biosynthetic REs is constitutively maintained by VAMP7, but can be promoted by synaptic activity in a VAMP2-dependent manner. These results provide crucial insight into membrane trafficking processes that could support experience-dependent learning by rapidly delivering locally synthesized proteins to synaptic locations. Ongoing efforts are focused on the development of novel optical approaches to control secretory trafficking that will ultimately expand our capability to dissect the spatial trafficking of cargoes within the dendrite.
Shaping The Postsynaptic Landscape Understanding The Role Of Neuronal Activity In Local Secretory And Endocytic Protein Trafficking Dynamics
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Author : Ashley M. Bourke
language : en
Publisher:
Release Date : 2018
Shaping The Postsynaptic Landscape Understanding The Role Of Neuronal Activity In Local Secretory And Endocytic Protein Trafficking Dynamics written by Ashley M. Bourke and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018 with categories.
Neuronal development, morphology, excitability and synapse function rely on the ability to maintain and dynamically regulate the repertoire of channel, receptor and adhesion integral membrane proteins presented on the cell surface with extraordinary spatiotemporal specificity. The requirement for the exact spatiotemporal control of surface protein abundance and spatial distribution is an especially tall order for neuronal cells given their immense size, intricate morphology and segregated domain structure. Precise regulation of biosynthetic and endocytic protein trafficking is further confounded by synaptic activity, and the polarization of the somatic Golgi apparatus (GA) presents an arduous undertaking by newly synthesized dendritic integral membrane proteins. How are these challenges reconciled with space- and time-sensitive protein movements to effectively sustain neuronal function? Where, when and how key synaptic receptor proteins are trafficked to and within remote dendritic domains to meet the exigent demands of the cell have remained fundamental yet challenging questions in neuronal cell biology. Recent findings from the Kennedy lab and others propose the existence of a compartmentalized secretory trafficking network in dendrites yet experimentally investigating the relevance of local vs. centralized trafficking pathways has been impossible because currently there is no way to selectively control forward secretory trafficking from distinct subcellular domains. Here I describe the development and implementation of an opto/chemogenetic approach that allows for local, light-triggered forward trafficking of endoplasmic reticulum (ER)-sequestered proteins from user-defined regions within the cell (e.g. the neuronal cell body vs. individual dendritic branches). We discovered that proteins originating in the cell body could be transported deep into dendrites before surface insertion, with distinct cargoes displaying strikingly different kinetics, spatial distributions and activity dependencies. Surprisingly, proteins entering the dendritic secretory pathway were rapidly dispersed before reaching the surface. Additionally, we discovered that select cargoes are rapidly inserted in the plasma membrane at the axon initial segment (AIS), demonstrating a previously unappreciated role of the AIS as a major forward trafficking hub even for somatodendritic cargoes. Finally, we demonstrate that activity may have opposite effects on subcellular targeting of cargoes processed through somatic and dendritic networks. Our results provide the first quantitative characterization of compartmentalized secretory trafficking, placing important experimental constraints on current models for long-range and local protein trafficking. Once newly delivered synaptic proteins arrive at their functional destinations on the dendritic spine PM, their abundance and spatial distribution can be maintained or drastically modified through their endocytic trafficking depending on the current activity state of the synapse. We hypothesized that local alterations to synapses are mediated in part by regulated trafficking of postsynaptic proteins through organelles called recycling endosomes (REs), which act as reservoirs for important postsynaptic molecules. REs are housed within a large fraction of dendritic spines, the major postsynaptic sites of excitatory neurotransmission, and are thus well-poised to rapidly respond to changes in local activity to modulate synaptic structure and function. Using optical techniques coupled with local synapse activation and inactivation, we discovered that the rate of constitutive cargo flux through REs bidirectionally scales with synaptic activity at individual synaptic sites. Additionally, we demonstrate that RE cargo trafficking is coupled to synaptic activity by NMDA receptors and extracellular calcium. Finally, we demonstrate the synapse-specific, activity-dependent internalization of AMPA-type glutamate receptor 1 (GluA1), a key synaptic protein and known RE cargo. Overall, we have developed a novel optical approach for controlling secretory trafficking and we have characterized how neuronal activity influences the spatiotemporal properties of secretory and endocytic protein trafficking within distinct neuronal sub-compartments. These results provide crucial insight into how membrane trafficking processes might establish, maintain and modulate the molecular composition of synapses to support diverse forms of experience-dependent plasticity. Ongoing efforts are focused on both the proteomic mapping of the RE as well as the application of our novel optical approach to control the secretory trafficking of endogenous proteins.
Molecular Biology Of The Cell
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Author : Bruce Alberts
language : en
Publisher:
Release Date : 2002
Molecular Biology Of The Cell written by Bruce Alberts and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2002 with Cytology categories.
Stochastic Processes In Cell Biology
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Author : Paul C. Bressloff
language : en
Publisher: Springer Nature
Release Date : 2022-01-04
Stochastic Processes In Cell Biology written by Paul C. Bressloff and has been published by Springer Nature this book supported file pdf, txt, epub, kindle and other format this book has been release on 2022-01-04 with Mathematics categories.
This book develops the theory of continuous and discrete stochastic processes within the context of cell biology. In the second edition the material has been significantly expanded, particularly within the context of nonequilibrium and self-organizing systems. Given the amount of additional material, the book has been divided into two volumes, with volume I mainly covering molecular processes and volume II focusing on cellular processes. A wide range of biological topics are covered in the new edition, including stochastic ion channels and excitable systems, molecular motors, stochastic gene networks, genetic switches and oscillators, epigenetics, normal and anomalous diffusion in complex cellular environments, stochastically-gated diffusion, active intracellular transport, signal transduction, cell sensing, bacterial chemotaxis, intracellular pattern formation, cell polarization, cell mechanics, biological polymers and membranes, nuclear structure and dynamics, biological condensates, molecular aggregation and nucleation, cellular length control, cell mitosis, cell motility, cell adhesion, cytoneme-based morphogenesis, bacterial growth, and quorum sensing. The book also provides a pedagogical introduction to the theory of stochastic and nonequilibrium processes – Fokker Planck equations, stochastic differential equations, stochastic calculus, master equations and jump Markov processes, birth-death processes, Poisson processes, first passage time problems, stochastic hybrid systems, queuing and renewal theory, narrow capture and escape, extreme statistics, search processes and stochastic resetting, exclusion processes, WKB methods, large deviation theory, path integrals, martingales and branching processes, numerical methods, linear response theory, phase separation, fluctuation-dissipation theorems, age-structured models, and statistical field theory. This text is primarily aimed at graduate students and researchers working in mathematical biology, statistical and biological physicists, and applied mathematicians interested in stochastic modeling. Applied probabilists should also find it of interest. It provides significant background material in applied mathematics and statistical physics, and introduces concepts in stochastic and nonequilibrium processes via motivating biological applications. The book is highly illustrated and contains a large number of examples and exercises that further develop the models and ideas in the body of the text. It is based on a course that the author has taught at the University of Utah for many years.
Trafficking Inside Cells
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Author : Nava Segev
language : en
Publisher: Springer Science & Business Media
Release Date : 2010-05-30
Trafficking Inside Cells written by Nava Segev and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2010-05-30 with Science categories.
This book covers the past, present and future of the intra-cellular trafficking field, which has made a quantum leap in the last few decades. It details how the field has developed and evolved as well as examines future directions.
Protein Trafficking In Neurons
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Author : Andrew J. Bean
language : en
Publisher: Elsevier
Release Date : 2006-10-27
Protein Trafficking In Neurons written by Andrew J. Bean and has been published by Elsevier this book supported file pdf, txt, epub, kindle and other format this book has been release on 2006-10-27 with Science categories.
The efficient delivery of cellular constituents to their proper location is of fundamental importance for all cells and is of particular interest to neuroscientists, because of the unique functions and complex architecture of neurons. Protein Trafficking in Neurons examines mechanisms of protein trafficking and the role of trafficking in neuronal functioning from development to plasticity to disease. The book is divided into seven sections that review mechanisms of protein transport, the role of protein trafficking in synapse formation, exo- and endocytosis, transport of receptors, trafficking of ion channels and transporters, comparison of trafficking mechanisms in neuronal vs. non-neuronal cell types, and the relationship between trafficking and neuronal diseases such as Alzheimer's, Huntington's and Prion Diseases. Provides a comprehensive examination of membrane/protein movement in neuronal function Sections on synapse development, synaptic transmission, and the role of trafficking in neurological disease Includes a focus on Molecular Mechanisms Illustrated with color summary pictures The only book examining protein trafficking and its functional implications, written by leaders in the field
Neuronal Growth And Plasticity
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Author : Motoy Kuno
language : en
Publisher: BRILL
Release Date : 1984
Neuronal Growth And Plasticity written by Motoy Kuno and has been published by BRILL this book supported file pdf, txt, epub, kindle and other format this book has been release on 1984 with Developmental neurology categories.
Transcription Regulation Brain Development And Homeostasis A Finely Tuned And Orchestrated Scenario In Physiology And Pathology
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Author : Estela Maris Muñoz
language : en
Publisher: Frontiers Media SA
Release Date : 2022-02-21
Transcription Regulation Brain Development And Homeostasis A Finely Tuned And Orchestrated Scenario In Physiology And Pathology written by Estela Maris Muñoz and has been published by Frontiers Media SA this book supported file pdf, txt, epub, kindle and other format this book has been release on 2022-02-21 with Science categories.
Green Fluorescent Protein
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Author : Martin Chalfie
language : en
Publisher: John Wiley & Sons
Release Date : 2005-11-18
Green Fluorescent Protein written by Martin Chalfie and has been published by John Wiley & Sons this book supported file pdf, txt, epub, kindle and other format this book has been release on 2005-11-18 with Science categories.
Since the discovery of the gene for green fluorescent protein (GFP), derived from jellyfish, this protein that emits a green glow has initiated a revolution in molecular biosciences. With this tool, it is now possible to visualize nearly any protein of interest in any cell or tissue of any species. Since the publication of the first edition, there have been tremendously significant technological advances, including development of new mutant variants. Proteins are now available in yellow and blue, and Novel Fluorescent Proteins (NFPs) have expanded their utility in developing biosensors, biological markers, and other biological applications. This updated, expanded new edition places emphasis on the rise of NFPs, including new chapters on NFP properties with detailed protocols, applications of GFPs and NFPs in industry research, and biosensors. This book provides a solid theoretical framework, along with detailed, practical guidance on use of GFPs and NFPs with discussion of potential pitfalls. The expert contributors provide real examples in showing how to tailor GFP/NFP to specific systems, maximize expression, and enhance detection.