Dynamin Superfamily at Pre- and Postsynapses: Master Regulators of Synaptic Transmission and Plasticity in Health and Disease

2020 ◽  
pp. 107385842097431
Author(s):  
Jorge Arriagada-Diaz ◽  
Lorena Prado-Vega ◽  
Ana M. Cárdenas Díaz ◽  
Alvaro O. Ardiles ◽  
Arlek M. Gonzalez-Jamett
Keyword(s):  
Synaptic Transmission ◽  
Neurological Disorders ◽  
Synaptic Vesicles ◽  
Cell Types ◽  
Master Regulators ◽  
Vesicle Recycling ◽  
Cytoskeleton Remodeling ◽  
The Central Nervous System ◽  
Health And Disease ◽  
Different Cell Types

Dynamin superfamily proteins (DSPs) comprise a large group of GTP-ases that orchestrate membrane fusion and fission, and cytoskeleton remodeling in different cell-types. At the central nervous system, they regulate synaptic vesicle recycling and signaling-receptor turnover, allowing the maintenance of synaptic transmission. In the presynapses, these GTP-ases control the recycling of synaptic vesicles influencing the size of the ready-releasable pool and the release of neurotransmitters from nerve terminals, whereas in the postsynapses, they are involved in AMPA-receptor trafficking to and from postsynaptic densities, supporting excitatory synaptic plasticity, and consequently learning and memory formation. In agreement with these relevant roles, an important number of neurological disorders are associated with mutations and/or dysfunction of these GTP-ases. Along the present review we discuss the importance of DSPs at synapses and their implication in different neuropathological contexts.

scholarly journals Mitochondrial DNA Heteroplasmy as an Informational Reservoir Dynamically Linked to Metabolic and Immunological Processes Associated with COVID-19 Neurological Disorders

2021 ◽  
Author(s):  
George B. Stefano ◽  
Richard M. Kream
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Neurological Disorders ◽  
Nuclear Dna ◽  
Mitochondrial Dynamics ◽  
Cell Types ◽  
Tissue Specific ◽  
Copy Numbers ◽  
The Central Nervous System ◽  
Mitochondrial Dna Heteroplasmy

AbstractMitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

scholarly journals Activity and cytosolic Na+ regulates synaptic vesicle endocytosis

2019 ◽  
Author(s):  
Yun Zhu ◽  
Dainan Li ◽  
Hai Huang
Keyword(s):  
Synaptic Transmission ◽  
High Frequency ◽  
Synaptic Vesicles ◽  
Glutamate Uptake ◽  
High Frequencies ◽  
Vesicle Recycling ◽  
Two Photon ◽  
Readily Releasable Pool ◽  
Content Change ◽  
Intracellular Ca

ABSTRACTRetrieval of synaptic vesicles via endocytosis is essential for maintaining sustained synaptic transmission, especially for neurons that fire action potentials at high frequencies. However, how activity regulates synaptic vesicles recycling is largely unknown. Here we report that Na+ substantially accumulated in the mouse calyx of Held terminals during repetitive high-frequency spiking. Elevated presynaptic Na+ accelerated both slow and rapid forms of endocytosis and facilitated endocytosis overshoot but did not affect the readily releasable pool size, Ca2+ influx, or exocytosis. To examine whether this facilitation of endocytosis is related to the Na+-dependent vesicular content change, we dialyzed increasing concentrations of glutamate into the presynaptic cytosol or blocked the vesicular glutamate uptake with bafilomycin and found the rate of endocytosis was not affected by regulating the glutamate content in the presynaptic terminal. Endocytosis is critically dependent on intracellular Ca2+, and the activity of Na+/Ca2+ exchanger (NCX) may be altered when the Na+ gradient is changed. However, neither NCX blocker nor change of extracellular Na+ concentration affected the endocytosis rate. Moreover, two-photon Ca2+ imaging showed that presynaptic Na+ did not affect the action potential-evoked intracellular Ca2+ transient and decay. Therefore, we revealed a novel mechanism of cytosolic Na+ in accelerating vesicle endocytosis. During high-frequency synaptic transmission, when large amounts of synaptic vesicles are fused, Na+ accumulated in terminals, facilitated vesicle recycling and sustained reliable synaptic transmission.

scholarly journals Mitochondrial Fission Protein 1: Emerging Roles in Organellar Form and Function in Health and Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Ugochukwu Kelvin Ihenacho ◽  
Kelsey A. Meacham ◽  
Megan Cleland Harwig ◽  
Michael E. Widlansky ◽  
R. Blake Hill
Keyword(s):  
Human Health ◽  
Neurological Disorders ◽  
Mitochondrial Fission ◽  
Cell Types ◽  
Mitochondrial Division ◽  
Form And Function ◽  
Health And Disease ◽  
Genetic Deletion ◽  
And Function

Mitochondrial fission protein 1 (Fis1) was identified in yeast as being essential for mitochondrial division or fission and subsequently determined to mediate human mitochondrial and peroxisomal fission. Yet, its exact functions in humans, especially in regard to mitochondrial fission, remains an enigma as genetic deletion of Fis1 elongates mitochondria in some cell types, but not others. Fis1 has also been identified as an important component of apoptotic and mitophagic pathways suggesting the protein may have multiple, essential roles. This review presents current perspectives on the emerging functions of Fis1 and their implications in human health and diseases, with an emphasis on Fis1’s role in both endocrine and neurological disorders.

scholarly journals Dual pools of actin at presynaptic terminals

2012 ◽  
Vol 107 (12) ◽  
pp. 3479-3492 ◽  
Author(s):  
Adam Bleckert ◽  
Huzefa Photowala ◽  
Simon Alford
Keyword(s):  
Synaptic Transmission ◽  
Synaptic Vesicle ◽  
Synaptic Vesicles ◽  
Repetitive Stimulation ◽  
Filamentous Actin ◽  
Cortical Actin ◽  
Vesicle Recycling ◽  
Latrunculin A ◽  
Kinetics Of

We investigated actin's function in vesicle recycling and exocytosis at lamprey synapses and show that FM1-43 puncta and phalloidin-labeled filamentous actin (F-actin) structures are colocalized, yet recycling vesicles are not contained within F-actin clusters. Additionally, phalloidin also labels a plasma membrane-associated cortical actin. Injection of fluorescent G-actin revealed activity-independent dynamic actin incorporation into presynaptic synaptic vesicle clusters but not into cortical actin. Latrunculin-A, which sequesters G-actin, dispersed vesicle-associated actin structures and prevented subsequent labeled G-actin and phalloidin accumulation at presynaptic puncta, yet cortical phalloidin labeling persisted. Dispersal of presynaptic F-actin structures by latrunculin-A did not disrupt vesicle clustering or recycling or alter the amplitude or kinetics of excitatory postsynaptic currents (EPSCs). However, it slightly enhanced release during repetitive stimulation. While dispersal of presynaptic actin puncta with latrunculin-A failed to disperse synaptic vesicles or inhibit synaptic transmission, presynaptic phalloidin injection blocked exocytosis and reduced endocytosis measured by action potential-evoked FM1-43 staining. Furthermore, phalloidin stabilization of only cortical actin following pretreatment with latrunculin-A was sufficient to inhibit synaptic transmission. Conversely, treatment of axons with jasplakinolide, which induces F-actin accumulation but disrupts F-actin structures in vivo, resulted in increased synaptic transmission accompanied by a loss of phalloidin labeling of cortical actin but no loss of actin labeling within vesicle clusters. Marked synaptic deficits seen with phalloidin stabilization of cortical F-actin, in contrast to the minimal effects of disruption of a synaptic vesicle-associated F-actin, led us to conclude that two structurally and functionally distinct pools of actin exist at presynaptic sites.

Neuroanatomy and neurophysiology

2021 ◽  
pp. 725-852
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cervical Vertebrae ◽  
Lymphatic Vessels ◽  
Cell Types ◽  
Cellular Level ◽  
Inhibitory Synapses ◽  
The Central Nervous System ◽  
Emotion Memory ◽  
Different Cell Types

‘Neuroanatomy and neurophysiology’ covers the anatomy and organization of the central nervous system, including the skull and cervical vertebrae, the meninges, the blood and lymphatic vessels, muscles and nerves of the head and neck, and the structures of the eye, ear, and central nervous system. At a cellular level, the different cell types and the mechanism of transmission across synapses are considered, including excitatory and inhibitory synapses. This is followed by a review of the major control and sensory systems (including movement, information processing, locomotion, reflexes, and the main five senses of sight, hearing, touch, taste, and smell). The integration of these processes into higher functions (such as sleep, consciousness and coma, emotion, memory, and ageing) is discussed, along with the causes and treatments of disorders of diseases such as depression, schizophrenia, epilepsy, addiction, and degenerative diseases.

scholarly journals Systems Biology and Kidney Disease

2020 ◽  
Vol 15 (5) ◽  
pp. 695-703 ◽  
Author(s):  
Jennifer A. Schaub ◽  
Habib Hamidi ◽  
Lalita Subramanian ◽  
Matthias Kretzler
Keyword(s):  
Systems Biology ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Clinical Care ◽  
Treatment Options ◽  
Cell Types ◽  
Current State ◽  
Health And Disease ◽  
National Databases ◽  
Different Cell Types

The kidney is a complex organ responsible for maintaining multiple aspects of homeostasis in the human body. The combination of distinct, yet interrelated, molecular functions across different cell types make the delineation of factors associated with loss or decline in kidney function challenging. Consequently, there has been a paucity of new diagnostic markers and treatment options becoming available to clinicians and patients in managing kidney diseases. A systems biology approach to understanding the kidney leverages recent advances in computational technology and methods to integrate diverse sets of data. It has the potential to unravel the interplay of multiple genes, proteins, and molecular mechanisms that drive key functions in kidney health and disease. The emergence of large, detailed, multilevel biologic and clinical data from national databases, cohort studies, and trials now provide the critical pieces needed for meaningful application of systems biology approaches in nephrology. The purpose of this review is to provide an overview of the current state in the evolution of the field. Recent successes of systems biology to identify targeted therapies linked to mechanistic biomarkers in the kidney are described to emphasize the relevance to clinical care and the outlook for improving outcomes for patients with kidney diseases.

Mucopolysaccharidosis in Adults

2016 ◽  
Author(s):  
Christian J. Hendriksz ◽  
Francois Karstens
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Autosomal Recessive ◽  
Clinical Symptoms ◽  
Cell Types ◽  
Type Ii ◽  
System P ◽  
Different Types ◽  
The Central Nervous System ◽  
Different Cell Types

There are 8 different types of diseases of the mucopolysaccharides, each caused by a deficiency in one of 10 different enzymes involved in the degradation of glycosaminoglycans (GAGs). Partially degraded GAGs accumulate within the lysosomes of many different cell types and lead to clinical symptoms and excretion of large amounts of GAGs in the urine. Heritability is autosomal recessive except for MPS type II, which is X-linked. The disorders are chronic and progressive and, although the specific types all have their individual features, they share an abundance of clinical similarities. All involve the musculoskeletal, the cardiovascular, the pulmonary and the central nervous system.

scholarly journals Mapping multicellular programs from single-cell profiles

2020 ◽  
Author(s):  
Livnat Jerby-Arnon ◽  
Aviv Regev
Keyword(s):  
Single Cell ◽  
Spatial Data ◽  
Spatial Information ◽  
Single Cells ◽  
Cell Types ◽  
Risk Genes ◽  
Health And Disease ◽  
Different Cell Types ◽  
Cellular Components ◽  
Acting In Concert

ABSTRACTTissue homeostasis relies on orchestrated multicellular circuits, where interactions between different cell types dynamically balance tissue function. While single-cell genomics identifies tissues’ cellular components, deciphering their coordinated action remains a major challenge. Here, we tackle this problem through a new framework of multicellular programs: combinations of distinct cellular programs in different cell types that are coordinated together in the tissue, thus forming a higher order functional unit at the tissue, rather than only cell, level. We develop the open-access DIALOGUE algorithm to systematically uncover such multi-cellular programs not only from spatial data, but even from tissue dissociated and profiled as single cells, e.g., by single-cell RNA-Seq. Tested on spatial transcriptomes from the mouse hypothalamus, DIALOGUE recovered spatial information, predicted the properties of a cell’s environment only based on its transcriptome, and identified multicellular programs that mark animal behavior. Applied to brain samples and colon biopsies profiled by scRNA-Seq, DIALOGUE identified multicellular configurations that mark Alzheimer’s disease and ulcerative colitis (UC), including a program spanning five cell types that is predictive of response to anti-TNF therapy in UC patients and enriched for UC risk genes from GWAS, each acting in different cell types, but all cells acting in concert. Taken together, our study provides a novel conceptual and methodological framework to unravel multicellular regulation in health and disease.

Cholesterol in Brain Development and Perinatal Brain Injury: more than a Building Block

2021 ◽  
Vol 19 ◽  
Author(s):  
Fuxin Lu ◽  
Donna M Ferriero ◽  
Xiangning Jiang
Keyword(s):  
Brain Injury ◽  
Brain Development ◽  
Cholesterol Biosynthesis ◽  
Cell Types ◽  
Cholesterol Homeostasis ◽  
Adult Brain ◽  
Brain Maturation ◽  
Perinatal Brain Injury ◽  
The Central Nervous System ◽  
Different Cell Types

: The central nervous system (CNS) is enriched with important classes of lipids, in which cholesterol is known to make up a major portion of myelin sheaths, besides being a structural and functional unit of CNS cell membranes. Unlike in the adult brain where the cholesterol pool is relatively stable, cholesterol is synthesized and accumulated at the highest rate in the developing brain to meet the needs of rapid brain growth at this stage, which is also a critical period for neuroplasticity. In addition to its biophysical role in membrane organization, cholesterol is crucial for brain development due to its involvement in brain patterning, myelination, neuronal differentiation and synaptogenesis. Thus any injuries to the immature brain that affect cholesterol homeostasis may have long-term adverse neurological consequences. In this review, we describe the unique features of brain cholesterol biosynthesis and metabolism, cholesterol trafficking between different cell types, and highlight cholesterol-dependent biological processes during brain maturation. We also discuss the association of impaired cholesterol homeostasis with several forms of perinatal brain disorders in term and preterm newborns, including hypoxic-ischemic encephalopathy. Strategies targeting the cholesterol pathways may open new avenues for diagnosis and treatment of developmental brain injury.

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