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Journal of the American Academy of... Apr 2020Hyperhidrosis is a dermatological condition defined by excessive sweating beyond thermoregulatory needs with significant effects on patients' quality of life.... (Review)
Review
Hyperhidrosis is a dermatological condition defined by excessive sweating beyond thermoregulatory needs with significant effects on patients' quality of life. Hyperhidrosis is categorized as primary or secondary: primary hyperhidrosis is mostly focal and idiopathic, whereas secondary hyperhidrosis is commonly generalized and caused by an underlying medical condition or use of medications. Various surgical and nonsurgical therapies exist for primary hyperhidrosis. Although botulinum toxin is one of the deadliest toxins known, when used in small doses, it is one of the most effective therapies for primary hyperhidrosis. Botulinum toxin injections are widely used as a second-line primary hyperhidrosis treatment option once topical treatment strategies have failed. This article provides an overview of the commercially available botulinum toxin formulations and their applications in the treatment of primary hyperhidrosis.
Topics: Acetylcholine; Acetylcholine Release Inhibitors; Axilla; Botulinum Toxins, Type A; Dose-Response Relationship, Drug; Exocytosis; Humans; Hyperhidrosis; Injection Site Reaction; Injections, Intradermal; Neuromuscular Junction; Presynaptic Terminals; Quality of Life; Sweat Glands; Treatment Outcome; United States
PubMed: 31811879
DOI: 10.1016/j.jaad.2019.11.042 -
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 -
Neuron Jul 2023In Alzheimer's disease, fibrillar tau pathology accumulates and spreads through the brain and synapses are lost. Evidence from mouse models indicates that tau spreads...
In Alzheimer's disease, fibrillar tau pathology accumulates and spreads through the brain and synapses are lost. Evidence from mouse models indicates that tau spreads trans-synaptically from pre- to postsynapses and that oligomeric tau is synaptotoxic, but data on synaptic tau in human brain are scarce. Here we used sub-diffraction-limit microscopy to study synaptic tau accumulation in postmortem temporal and occipital cortices of human Alzheimer's and control donors. Oligomeric tau is present in pre- and postsynaptic terminals, even in areas without abundant fibrillar tau deposition. Furthermore, there is a higher proportion of oligomeric tau compared with phosphorylated or misfolded tau found at synaptic terminals. These data suggest that accumulation of oligomeric tau in synapses is an early event in pathogenesis and that tau pathology may progress through the brain via trans-synaptic spread in human disease. Thus, specifically reducing oligomeric tau at synapses may be a promising therapeutic strategy for Alzheimer's disease.
Topics: Animals; Humans; Mice; Alzheimer Disease; Amyloid beta-Peptides; Brain; Presynaptic Terminals; Synapses; tau Proteins
PubMed: 37192625
DOI: 10.1016/j.neuron.2023.04.020 -
Neuron Jan 2021Neurons are known to rely on autophagy for removal of defective proteins or organelles to maintain synaptic neurotransmission and counteract neurodegeneration. In spite...
Neurons are known to rely on autophagy for removal of defective proteins or organelles to maintain synaptic neurotransmission and counteract neurodegeneration. In spite of its importance for neuronal health, the physiological substrates of neuronal autophagy in the absence of proteotoxic challenge have remained largely elusive. We use knockout mice conditionally lacking the essential autophagy protein ATG5 and quantitative proteomics to demonstrate that loss of neuronal autophagy causes selective accumulation of tubular endoplasmic reticulum (ER) in axons, resulting in increased excitatory neurotransmission and compromised postnatal viability in vivo. The gain in excitatory neurotransmission is shown to be a consequence of elevated calcium release from ER stores via ryanodine receptors accumulated in axons and at presynaptic sites. We propose a model where neuronal autophagy controls axonal ER calcium stores to regulate neurotransmission in healthy neurons and in the brain.
Topics: Animals; Autophagy; Axons; Endoplasmic Reticulum; Excitatory Postsynaptic Potentials; Hippocampus; Mice; Mice, 129 Strain; Mice, Knockout; Mice, Transgenic; Neurons; Organ Culture Techniques; Presynaptic Terminals; Synaptic Transmission
PubMed: 33157003
DOI: 10.1016/j.neuron.2020.10.005 -
Cell Apr 2024In addition to long-distance molecular motor-mediated transport, cellular vesicles also need to be moved at short distances with defined directions to meet functional...
In addition to long-distance molecular motor-mediated transport, cellular vesicles also need to be moved at short distances with defined directions to meet functional needs in subcellular compartments but with unknown mechanisms. Such short-distance vesicle transport does not involve molecular motors. Here, we demonstrate, using synaptic vesicle (SV) transport as a paradigm, that phase separation of synaptic proteins with vesicles can facilitate regulated, directional vesicle transport between different presynaptic bouton sub-compartments. Specifically, a large coiled-coil scaffold protein Piccolo, in response to Ca and via its C2A domain-mediated Ca sensing, can extract SVs from the synapsin-clustered reserve pool condensate and deposit the extracted SVs onto the surface of the active zone protein condensate. We further show that the Trk-fused gene, TFG, also participates in COPII vesicle trafficking from ER to the ER-Golgi intermediate compartment via phase separation. Thus, phase separation may play a general role in short-distance, directional vesicle transport in cells.
Topics: Animals; Synaptic Vesicles; COP-Coated Vesicles; Endoplasmic Reticulum; Calcium; Golgi Apparatus; Rats; Biological Transport; Presynaptic Terminals; Synapsins; Biomolecular Condensates; Cytoskeletal Proteins; Phase Separation
PubMed: 38552623
DOI: 10.1016/j.cell.2024.03.003 -
Nature Neuroscience Mar 2020Emerging evidence indicates that liquid-liquid phase separation, the formation of a condensed molecular assembly within another diluted aqueous solution, is a means for... (Review)
Review
Emerging evidence indicates that liquid-liquid phase separation, the formation of a condensed molecular assembly within another diluted aqueous solution, is a means for cells to organize highly condensed biological assemblies (also known as biological condensates or membraneless compartments) with very broad functions and regulatory properties in different subcellular regions. Molecular machineries dictating synaptic transmissions in both presynaptic boutons and postsynaptic densities of neuronal synapses may be such biological condensates. Here we review recent developments showing how phase separation can build dense synaptic molecular clusters, highlight unique features of such condensed clusters in the context of synaptic development and signaling, discuss how aberrant phase-separation-mediated synaptic assembly formation may contribute to dysfunctional signaling in psychiatric disorders, and present some challenges and opportunities of phase separation in synaptic biology.
Topics: Animals; Humans; Post-Synaptic Density; Presynaptic Terminals; Synapses; Synaptic Transmission
PubMed: 32015539
DOI: 10.1038/s41593-019-0579-9 -
Nature Neuroscience Aug 2022Optogenetic actuators enable highly precise spatiotemporal interrogation of biological processes at levels ranging from the subcellular to cells, circuits and behaving... (Review)
Review
Optogenetic actuators enable highly precise spatiotemporal interrogation of biological processes at levels ranging from the subcellular to cells, circuits and behaving organisms. Although their application in neuroscience has traditionally focused on the control of spiking activity at the somatodendritic level, the scope of optogenetic modulators for direct manipulation of presynaptic functions is growing. Presynaptically localized opsins combined with light stimulation at the terminals allow light-mediated neurotransmitter release, presynaptic inhibition, induction of synaptic plasticity and specific manipulation of individual components of the presynaptic machinery. Here, we describe presynaptic applications of optogenetic tools in the context of the unique cell biology of axonal terminals, discuss their potential shortcomings and outline future directions for this rapidly developing research area.
Topics: Neuronal Plasticity; Opsins; Optogenetics; Presynaptic Terminals; Synaptic Transmission
PubMed: 35835882
DOI: 10.1038/s41593-022-01113-6 -
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 -
International Journal of Molecular... Mar 2022The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors. To meet these energetic... (Review)
Review
The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors. To meet these energetic requirements, the brain primarily uses glucose, which can be metabolized through glycolysis and/or mitochondrial oxidative phosphorylation. The relevance of these two energy production pathways in fulfilling energy at presynaptic terminals has been the subject of recent studies. In this review, we dissect the balance of glycolysis and oxidative phosphorylation to meet synaptic energy demands in both resting and stimulation conditions. Besides ATP output needs, mitochondria at synapse are also important for calcium buffering and regulation of reactive oxygen species. These two mitochondrial-associated pathways, once hampered, impact negatively on neuronal homeostasis and synaptic activity. Therefore, as mitochondria assume a critical role in synaptic homeostasis, it is becoming evident that the synaptic mitochondria population possesses a distinct functional fingerprint compared to other brain mitochondria. Ultimately, dysregulation of synaptic bioenergetics through glycolytic and mitochondrial dysfunctions is increasingly implicated in neurodegenerative disorders, as one of the first hallmarks in several of these diseases are synaptic energy deficits, followed by synapse degeneration.
Topics: Animals; Brain; Energy Metabolism; Mammals; Presynaptic Terminals; Synapses; Synaptic Transmission
PubMed: 35408993
DOI: 10.3390/ijms23073627 -
Trends in Neurosciences Jul 2021The concentration of calcium ions in presynaptic terminals regulates transmitter release, but underlying mechanisms have remained unclear. Here we review recent studies... (Review)
Review
The concentration of calcium ions in presynaptic terminals regulates transmitter release, but underlying mechanisms have remained unclear. Here we review recent studies that shed new light on this issue. Fast-freezing electron microscopy and total internal reflection fluorescence microscopy studies reveal complex calcium-dependent vesicle movements including docking on a millisecond time scale. Recordings from so-called 'simple synapses' indicate that calcium not only triggers exocytosis, but also modifies synaptic strength by controlling a final, rapid vesicle maturation step before release. Molecular studies identify several calcium-sensitive domains on Munc13 and on synaptotagmin-1 that are likely involved in bringing the vesicular and plasma membranes closer together in response to calcium elevation. Together, these results suggest that calcium-dependent vesicle docking occurs in a wide range of time domains and plays a crucial role in several phenomena including synaptic facilitation, post-tetanic potentiation, and neuromodulator-induced potentiation.
Topics: Calcium; Exocytosis; Humans; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 34049722
DOI: 10.1016/j.tins.2021.04.003