scholarly journals A sticky situation: regulation and function of protein palmitoylation with a spotlight on the axon and axon initial segment

2021 ◽  
Vol 5 (4) ◽  
Author(s):  
Andrey A. Petropavlovskiy ◽  
Jordan A. Kogut ◽  
Arshia Leekha ◽  
Charlotte A. Townsend ◽  
Shaun S. Sanders
Keyword(s):  
Protein Trafficking ◽  
Lipid Membranes ◽  
Initial Segment ◽  
Protein Targeting ◽  
Neurological Diseases ◽  
Axon Initial Segment ◽  
Neuronal Proteins ◽  
Dependent Protein ◽  
Specific Proteins ◽  
And Function

Abstract In neurons, the axon and axon initial segment (AIS) are critical structures for action potential initiation and propagation. Their formation and function rely on tight compartmentalisation, a process where specific proteins are trafficked to and retained at distinct subcellular locations. One mechanism which regulates protein trafficking and association with lipid membranes is the modification of protein cysteine residues with the 16-carbon palmitic acid, known as S-acylation or palmitoylation. Palmitoylation, akin to phosphorylation, is reversible, with palmitate cycling being mediated by substrate-specific enzymes. Palmitoylation is well-known to be highly prevalent among neuronal proteins and is well studied in the context of the synapse. Comparatively, how palmitoylation regulates trafficking and clustering of axonal and AIS proteins remains less understood. This review provides an overview of the current understanding of the biochemical regulation of palmitoylation, its involvement in various neurological diseases, and the most up-to-date perspective on axonal palmitoylation. Through a palmitoylation analysis of the AIS proteome, we also report that an overwhelming proportion of AIS proteins are likely palmitoylated. Overall, our review and analysis confirm a central role for palmitoylation in the formation and function of the axon and AIS and provide a resource for further exploration of palmitoylation-dependent protein targeting to and function at the AIS.

scholarly journals Homeostatic plasticity rules control the wiring of axo-axonic synapses at the axon initial segment

2018 ◽  
Author(s):  
Alejandro Pan-Vazquez ◽  
Winnie Wefelmeyer ◽  
Victoria Gonzalez Sabater ◽  
Juan Burrone
Keyword(s):  
Initial Segment ◽  
Pyramidal Cells ◽  
Axon Initial Segment ◽  
Homeostatic Plasticity ◽  
Network Activity ◽  
Gabaergic Interneuron ◽  
Chandelier Cells ◽  
Local Circuits ◽  
And Function

AbstractGABAergic interneurons are chiefly responsible for controlling the activity of local circuits in the cortex1,2. However, the rules that govern the wiring of interneurons are not well understood3. Chandelier cells (ChCs) are a type of GABAergic interneuron that control the output of hundreds of neighbouring pyramidal cells through axo-axonic synapses which target the axon initial segment (AIS)4. Despite their importance in modulating circuit activity, our knowledge of the development and function of axo-axonic synapses remains elusive. In this study, we investigated the role of activity in the formation and plasticity of ChC synapses. In vivo imaging of ChCs during development uncovered a narrow window (P12-P18) over which axons arborized and formed connections. We found that increases in the activity of either pyramidal cells or individual ChCs during this temporal window resulted in a reversible decrease in axo-axonic connections. Voltage imaging of GABAergic transmission at the AIS showed that axo-axonic synapses were depolarising during this period. Identical manipulations of network activity in older mice (P40-P46), when ChC synapses are inhibitory, resulted in an increase in axo-axonic synapses. We propose that the direction of ChC plasticity follows homeostatic rules that depend on the polarity of axo-axonic synapses.

scholarly journals Tropomyosin Tpm3.1 is required to maintain the structure and function of the axon initial segment

2019 ◽  
Author(s):  
Amr Abouelezz ◽  
Holly Stefen ◽  
Mikael Segerstråle ◽  
David Micinski ◽  
Rimante Minkeviciene ◽  
...  
Keyword(s):  
Actin Filaments ◽  
Hippocampal Neurons ◽  
Initial Segment ◽  
Actin Polymerization ◽  
Firing Frequency ◽  
Axon Initial Segment ◽  
Action Potential Initiation ◽  
Sodium Ion Channels ◽  
And Function ◽  
Filament Network

ABSTRACTThe axon initial segment (AIS) is the site of action potential initiation and serves as a vesicular filter and diffusion barrier that help maintain neuronal polarity. Recent studies have revealed details about a specialized structural complex in the AIS. While an intact actin cytoskeleton is required for AIS formation, pharmacological disruption of actin polymerization compromises the AIS vesicle filter but does not affect overall AIS structure. In this study, we found that the tropomyosin isoform Tpm3.1 decorates a population of relatively stable actin filaments in the AIS. Inhibiting Tpm3.1 in cultured hippocampal neurons led to the loss of AIS structure, the AIS vesicle filter, the clustering of sodium ion channels, and reduced firing frequency. We propose that Tpm3.1-decorated actin filaments form a stable actin filament network under the AIS membrane which provides a scaffold for membrane organization and AIS proteins.

scholarly journals Tropomyosin Tpm3.1 Is Required to Maintain the Structure and Function of the Axon Initial Segment

iScience ◽  
2020 ◽  
Vol 23 (5) ◽  
pp. 101053
Author(s):  
Amr Abouelezz ◽  
Holly Stefen ◽  
Mikael Segerstråle ◽  
David Micinski ◽  
Rimante Minkeviciene ◽  
...  
Keyword(s):  
Initial Segment ◽  
Structure And Function ◽  
Axon Initial Segment ◽  
And Function

scholarly journals Btn3 is a negative regulator of Btn2-mediated endosomal protein trafficking and prion curing in yeast

2011 ◽  
Vol 22 (10) ◽  
pp. 1648-1663 ◽  
Author(s):  
Vydehi Kanneganti ◽  
Rachel Kama ◽  
Jeffrey E. Gerst
Keyword(s):  
Protein Trafficking ◽  
Complex I ◽  
Protein Localization ◽  
Batten Disease ◽  
Negative Regulator ◽  
Interacting Protein ◽  
Complex I Deficiency ◽  
Specific Proteins ◽  
Deficiency Gene ◽  
And Function

Yeast Btn2 facilitates the retrieval of specific proteins from late endosomes (LEs) to the Golgi, a process that may be adversely affected in Batten disease patients. We isolated the putative yeast orthologue of a human complex I deficiency gene, designated here as BTN3, as encoding a Btn2-interacting protein and negative regulator. First, yeast overexpressing BTN3 phenocopy the deletion of BTN2 and mislocalize certain trans-Golgi proteins, like Kex2 and Yif1, to the LE and vacuole, respectively. In contrast, the deletion of BTN3 results in a tighter pattern of protein localization to the Golgi. Second, BTN3 overexpression alters Btn2 localization from the IPOD compartment, which correlates with a sharp reduction in Btn2-mediated [URE3] prion curing. Third, Btn3 and the Snc1 v-SNARE compete for the same binding domain on Btn2, and this competition controls Btn2 localization and function. The inhibitory effects upon protein retrieval and prion curing suggest that Btn3 sequesters Btn2 away from its substrates, thus down-regulating protein trafficking and aggregation. Therefore Btn3 is a novel negative regulator of intracellular protein sorting, which may be of importance in the onset of complex I deficiency and Batten disease in humans.

scholarly journals Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

2021 ◽  
Author(s):  
Pernille Bülow ◽  
Peter A Wenner ◽  
Victor Faundez ◽  
Gary J Bassell
Keyword(s):  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Neuronal Plasticity ◽  
Cortical Neurons ◽  
Initial Segment ◽  
Fragile X ◽  
Axon Initial Segment ◽  
Homeostatic Plasticity ◽  
Mitochondrial Morphology ◽  
And Function

Abstract Mitochondrial dysfunction has long been overlooked in neurodevelopmental disorders, but recent studies have provided new links to genetic forms of autism, including Rett syndrome and Fragile X Syndrome (FXS). In parallel, recent studies have uncovered important basic functions of mitochondria to power protein synthesis, synaptic plasticity and neuronal maturation. The mitochondrion also responds to neuronal activity by altering its morphology and function, and this plasticity of the mitochondrion appear important for proper neuronal plasticity. Previous research has reported disease induced changes in mitochondrial morphology and function, but it remains unknown how such abnormalities affect the ability of mitochondria to express activity dependent plasticity. This study addresses this gap in knowledge using a mouse model of FXS. We previously reported abnormalities in one type of homeostatic plasticity, called homeostatic intrinsic plasticity, which is known to involve structural changes in the axon initial segment (AIS). Another form of homeostatic plasticity, called synaptic scaling, which involves postsynaptic changes in dendrites, is also impaired in FXS. It remains unknown if or how homeostatic plasticity affects mitochondria in axons and/or dendrites and whether impairments occur in neurodevelopmental disorders. Here, we test the hypothesis that mitochondria are structurally and functionally modified in a compartment specific manner during homeostatic plasticity in cortical neurons from wild type mice, and that this plasticity-induced regulation is altered in Fmr1 KO neurons, as a model of FXS. We uncovered dendritic specific regulation of mitochondrial surface area, whereas AIS mitochondria show changes in polarity; both responses are lost in Fmr1 KO. Taken together our results demonstrate impairments in mitochondrial plasticity in FXS, which has not previously been reported. These results suggest that mitochondrial dysregulation in FXS contributes to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.

scholarly journals Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment Are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

2021 ◽  
Vol 9 ◽  
Author(s):  
Pernille Bülow ◽  
Peter A. Wenner ◽  
Victor Faundez ◽  
Gary J. Bassell
Keyword(s):  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Cortical Neurons ◽  
Initial Segment ◽  
Fragile X ◽  
Axon Initial Segment ◽  
Homeostatic Plasticity ◽  
Mitochondrial Morphology ◽  
Specific Regulation ◽  
And Function

Mitochondrial dysfunction has long been overlooked in neurodevelopmental disorders, but recent studies have provided new links to genetic forms of autism, including Rett syndrome and fragile X syndrome (FXS). Mitochondria show plasticity in morphology and function in response to neuronal activity, and previous research has reported impairments in mitochondrial morphology and function in disease. We and others have previously reported abnormalities in distinct types of homeostatic plasticity in FXS. It remains unknown if or how activity deprivation triggering homeostatic plasticity affects mitochondria in axons and/or dendrites and whether impairments occur in neurodevelopmental disorders. Here, we test the hypothesis that mitochondria are structurally and functionally modified in a compartment-specific manner during homeostatic plasticity using a model of activity deprivation in cortical neurons from wild-type mice and that this plasticity-induced regulation is altered in Fmr1-knockout (KO) neurons. We uncovered dendrite-specific regulation of the mitochondrial surface area, whereas axon initial segment (AIS) mitochondria show changes in polarity; both responses are lost in the Fmr1 KO. Taken together, our results demonstrate impairments in mitochondrial plasticity in FXS, which has not previously been reported. These results suggest that mitochondrial dysregulation in FXS could contribute to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.

scholarly journals Assembly and Function of the Juxtaparanodal Kv1 Complex in Health and Disease

Life ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 8
Author(s):  
Delphine Pinatel ◽  
Catherine Faivre-Sarrailh
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecules ◽  
Cell Adhesion Molecules ◽  
Initial Segment ◽  
Axon Initial Segment ◽  
Health And Disease ◽  
Low Threshold ◽  
Frequency Of Action Potentials ◽  
And Function ◽  
Spike Initiation

The precise axonal distribution of specific potassium channels is known to secure the shape and frequency of action potentials in myelinated fibers. The low-threshold voltage-gated Kv1 channels located at the axon initial segment have a significant influence on spike initiation and waveform. Their role remains partially understood at the juxtaparanodes where they are trapped under the compact myelin bordering the nodes of Ranvier in physiological conditions. However, the exposure of Kv1 channels in de- or dys-myelinating neuropathy results in alteration of saltatory conduction. Moreover, cell adhesion molecules associated with the Kv1 complex, including Caspr2, Contactin2, and LGI1, are target antigens in autoimmune diseases associated with hyperexcitability such as encephalitis, neuromyotonia, or neuropathic pain. The clustering of Kv1.1/Kv1.2 channels at the axon initial segment and juxtaparanodes is based on interactions with cell adhesion molecules and cytoskeletal linkers. This review will focus on the trafficking and assembly of the axonal Kv1 complex in the peripheral and central nervous system (PNS and CNS), during development, and in health and disease.

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