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Trends in Neurosciences Feb 2023α-Synuclein is a neuronal protein that is enriched in presynaptic terminals. Under physiological conditions, it binds to synaptic vesicle membranes and functions in... (Review)
Review
α-Synuclein is a neuronal protein that is enriched in presynaptic terminals. Under physiological conditions, it binds to synaptic vesicle membranes and functions in neurotransmitter release, although the molecular details remain unclear, and it is controversial whether α-synuclein inhibits or facilitates neurotransmitter release. Pathologically, in synucleinopathies including Parkinson's disease (PD), α-synuclein forms aggregates that recruit monomeric α-synuclein and spread throughout the brain, which triggers neuronal dysfunction at molecular, cellular, and organ levels. Here, we present an overview of the effects of α-synuclein on SNARE-complex assembly, neurotransmitter release, and synaptic vesicle pool homeostasis, and discuss how the observed divergent effects of α-synuclein on neurotransmitter release can be reconciled. We also discuss how gain-of-function versus loss-of-function of α-synuclein may contribute to pathogenesis in synucleinopathies.
Topics: Humans; alpha-Synuclein; Synucleinopathies; Parkinson Disease; Synaptic Vesicles; Neurotransmitter Agents
PubMed: 36567199
DOI: 10.1016/j.tins.2022.11.007 -
Science (New York, N.Y.) Oct 2023Neurons relay information via specialized presynaptic compartments for neurotransmission. Unlike conventional organelles, the specialized apparatus characterizing the...
Neurons relay information via specialized presynaptic compartments for neurotransmission. Unlike conventional organelles, the specialized apparatus characterizing the neuronal presynapse must form de novo. How the components for presynaptic neurotransmission are transported and assembled is poorly understood. Our results show that the rare late endosomal signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P] directs the axonal cotransport of synaptic vesicle and active zone proteins in precursor vesicles in human neurons. Precursor vesicles are distinct from conventional secretory organelles, endosomes, and degradative lysosomes and are transported by coincident detection of PI(3,5)P and active ARL8 via kinesin KIF1A to the presynaptic compartment. Our findings identify a crucial mechanism that mediates the delivery of synaptic vesicle and active zone proteins to developing synapses.
Topics: Humans; Axonal Transport; Kinesins; Neurons; Synaptic Vesicles; Phosphatidylinositol Phosphates
PubMed: 37824668
DOI: 10.1126/science.adg1075 -
Neuron Mar 2022Autophagy is a cellular degradation pathway essential for neuronal health and function. Autophagosome biogenesis occurs at synapses, is locally regulated, and increases...
Autophagy is a cellular degradation pathway essential for neuronal health and function. Autophagosome biogenesis occurs at synapses, is locally regulated, and increases in response to neuronal activity. The mechanisms that couple autophagosome biogenesis to synaptic activity remain unknown. In this study, we determine that trafficking of ATG-9, the only transmembrane protein in the core autophagy pathway, links the synaptic vesicle cycle with autophagy. ATG-9-positive vesicles in C. elegans are generated from the trans-Golgi network via AP-3-dependent budding and delivered to presynaptic sites. At presynaptic sites, ATG-9 undergoes exo-endocytosis in an activity-dependent manner. Mutations that disrupt endocytosis, including a lesion in synaptojanin 1 associated with Parkinson's disease, result in abnormal ATG-9 accumulation at clathrin-rich synaptic foci and defects in activity-induced presynaptic autophagy. Our findings uncover regulated key steps of ATG-9 trafficking at presynaptic sites and provide evidence that ATG-9 exo-endocytosis couples autophagosome biogenesis at presynaptic sites with the activity-dependent synaptic vesicle cycle.
Topics: Animals; Autophagy; Autophagy-Related Proteins; Caenorhabditis elegans; Endocytosis; Presynaptic Terminals; Synaptic Vesicles
PubMed: 35065714
DOI: 10.1016/j.neuron.2021.12.031 -
Neuroscience Letters Apr 2019As the sites of communication between neurons, synapses depend upon precisely regulated protein-protein interactions to support neurotransmitter release and reception.... (Review)
Review
As the sites of communication between neurons, synapses depend upon precisely regulated protein-protein interactions to support neurotransmitter release and reception. Moreover, neuronal synapses typically exist great distances (i.e. up to meters) away from cell bodies, which are the sources of new proteins and the major sites of protein degradation via lysosomes. Thus, synapses are uniquely sensitive to disruptions in proteostasis, and depend upon carefully orchestrated degradative mechanisms for the clearance of dysfunctional proteins. One of the primary cellular degradative pathways is macroautophagy, hereafter referred to as 'autophagy'. Although it has only recently become a focus of research in synaptic biology, emerging studies indicate that autophagy has essential functions at the synapse throughout an organism's lifetime. This review will discuss recent findings about the roles of synaptic autophagy, as well as some of the questions and issues to be considered in this field moving forward.
Topics: Animals; Autophagy; Humans; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 29802916
DOI: 10.1016/j.neulet.2018.05.033 -
Current Biology : CB Nov 2014Synapses are specialized asymmetric cell-cell connections permitting the controlled transfer of an electrical or chemical signal between a presynaptic neuronal cell and...
Synapses are specialized asymmetric cell-cell connections permitting the controlled transfer of an electrical or chemical signal between a presynaptic neuronal cell and a postsynaptic target cell (e.g. neuron or muscle). Adequate synapse function is an essential prerequisite of all neuronal processing, including higher cognitive functions, such as learning and memory. At synapses, neurotransmitters (e.g. amino acids, amines, peptides, and acetylcholine) are released from synaptic vesicles into the synaptic cleft in response to action potentials. The Nobel Prize for Physiology and Medicine in 2013 was awarded to James E. Rothman, Randy W. Schekman and Thomas C. Südhof "for their discoveries of the machinery regulating vesicle traffic, a major transport system in our cells". This included crucial revelations, such as the identification of the core machinery of synaptic vesicle fusion. However, in contrast to the advances concerning the organization of the core functions of the synapse, our current understanding of the processes of synapse formation and maintenance--i.e. 'synaptogenesis'--is still somewhat fragmentary. Here, we will outline the current status and future directions of the field of synaptogenesis, primarily from the perspective of the presynaptic release site.
Topics: Biological Transport; Models, Biological; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 25458214
DOI: 10.1016/j.cub.2014.10.024 -
Current Opinion in Structural Biology Feb 2019Here, we review recent insights into the neuronal presynaptic fusion machinery that releases neurotransmitter molecules into the synaptic cleft upon stimulation. The... (Review)
Review
Here, we review recent insights into the neuronal presynaptic fusion machinery that releases neurotransmitter molecules into the synaptic cleft upon stimulation. The structure of the pre-fusion state of the SNARE/complexin-1/synaptotagmin-1 synaptic protein complex suggests a new model for the initiation of fast Ca-triggered membrane fusion. Functional studies have revealed roles of the essential factors Munc18 and Munc13, demonstrating that a part of their function involves the proper assembly of synaptic protein complexes. Near-atomic resolution structures of the NSF/αSNAP/SNARE complex provide first glimpses of the molecular machinery that disassembles the SNARE complex during the synaptic vesicle cycle. These structures show how this machinery captures the SNARE substrate and provide clues as to a possible processing mechanism.
Topics: Animals; Calcium; Humans; SNARE Proteins; Synapses; Synaptic Vesicles
PubMed: 30986753
DOI: 10.1016/j.sbi.2019.03.007 -
Cell Calcium Jan 2020Synaptic transmission relies on rapid calcium (Ca) influx into presynaptic terminal via voltage-gated Ca channels. However, smooth ER is present in presynaptic terminals... (Review)
Review
Synaptic transmission relies on rapid calcium (Ca) influx into presynaptic terminal via voltage-gated Ca channels. However, smooth ER is present in presynaptic terminals and accumulating evidence indicate that ER Ca signaling may play a modulatory role in synaptic transmission. Most recent publication by Lindhout and colleagues (EMBO J, 38 (2019) e101345) suggested that the fragmentation state of the ER affects synaptic vesicle release. Here we discuss these results as well as several key publications that addressed a connection between ER Ca signaling and synaptic transmission.
Topics: Animals; Calcium; Endoplasmic Reticulum; Humans; Models, Biological; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 31812114
DOI: 10.1016/j.ceca.2019.102133 -
Journal of Neurochemistry Apr 2021The revolution in genetic technology has ushered in a new age for our understanding of the underlying causes of neurodevelopmental, neuromuscular and neurodegenerative... (Review)
Review
The revolution in genetic technology has ushered in a new age for our understanding of the underlying causes of neurodevelopmental, neuromuscular and neurodegenerative disorders, revealing that the presynaptic machinery governing synaptic vesicle fusion is compromised in many of these neurological disorders. This builds upon decades of research showing that disturbance to neurotransmitter release via toxins can cause acute neurological dysfunction. In this review, we focus on disorders of synaptic vesicle fusion caused either by toxic insult to the presynapse or alterations to genes encoding the key proteins that control and regulate fusion: the SNARE proteins (synaptobrevin, syntaxin-1 and SNAP-25), Munc18, Munc13, synaptotagmin, complexin, CSPα, α-synuclein, PRRT2 and tomosyn. We discuss the roles of these proteins and the cellular and molecular mechanisms underpinning neurological deficits in these disorders.
Topics: Animals; Exocytosis; Humans; Membrane Fusion; Neurons; Synaptic Transmission; Synaptic Vesicles; Synaptotagmins
PubMed: 32916768
DOI: 10.1111/jnc.15181 -
Trends in Neurosciences Apr 2023Neuronal communication crucially relies on exocytosis of neurotransmitters from synaptic vesicles (SVs) which are clustered at synapses. To ensure reliable... (Review)
Review
Neuronal communication crucially relies on exocytosis of neurotransmitters from synaptic vesicles (SVs) which are clustered at synapses. To ensure reliable neurotransmitter release, synapses need to maintain an adequate pool of SVs at all times. Decades of research have established that SVs are clustered by synapsin 1, an abundant SV-associated phosphoprotein. The classical view postulates that SVs are crosslinked in a scaffold of protein-protein interactions between synapsins and their binding partners. Recent studies have shown that synapsins cluster SVs via liquid-liquid phase separation (LLPS), thus providing a new framework for the organization of the synapse. We discuss the evidence for phase separation of SVs, emphasizing emerging questions related to its regulation, specificity, and reversibility.
Topics: Humans; Synaptic Vesicles; Synapsins; Synapses; Synaptic Transmission; Biology
PubMed: 36725404
DOI: 10.1016/j.tins.2023.01.001 -
Advances in Biological Regulation Jan 2017Lipids play a vital role in the health and functioning of neurons and interest in the physiological role of neuronal lipids is certainly increasing. One neuronal... (Review)
Review
Lipids play a vital role in the health and functioning of neurons and interest in the physiological role of neuronal lipids is certainly increasing. One neuronal function in which neuronal lipids appears to play key roles in neurotransmission. Our understanding of the role of lipids in the synaptic vesicle cycle and neurotransmitter release is becoming increasingly more important. Much of the initial research in this area has highlighted the major roles played by the phosphoinositides (PtdIns), diacylglycerol (DAG), and phosphatidic acid (PtdOH). Of these, PtdOH has not received as much attention as the other lipids although its role and metabolism appears to be extremely important. This lipid has been shown to play a role in modulating both exocytosis and endocytosis although its precise role in either process is not well defined. The currently evidence suggest this lipid likely participates in key processes by altering membrane architecture necessary for membrane fusion, mediating the penetration of membrane proteins, serving as a precursor for other important SV cycling lipids, or activating essential enzymes. In this review, we address the sources of PtdOH, the enzymes involved in its production, the regulation of these enzymes, and its potential roles in neurotransmission in the central nervous system.
Topics: Animals; Biological Transport; Cell Membrane; Central Nervous System; Diglycerides; Endocytosis; Exocytosis; Humans; Lipid Metabolism; Neurons; Phosphatidic Acids; Phosphatidylinositol 4,5-Diphosphate; Synaptic Transmission; Synaptic Vesicles
PubMed: 27671966
DOI: 10.1016/j.jbior.2016.09.004