scholarly journals Syntaxins 6 and 8 facilitate tau into secretory pathways

2021 ◽  
Author(s):  
Wei Siang Lee ◽  
Daniel CS Tan ◽  
Yuanyuan Deng ◽  
Annika van Hummel ◽  
Stefania Ippati ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Molecular Mechanisms ◽  
Transmembrane Domain ◽  
Brain Regions ◽  
Tau Pathology ◽  
Tail Region ◽  
Secretory Pathways ◽  
Donor Cells ◽  
Neuronal Connections

Tau pathology initiates in defined brain regions and is known to spread along neuronal connections as symptoms progress in Alzheimer’s disease (AD) and other tauopathies. This spread requires the release of tau from donor cells, but the underlying molecular mechanisms remained unknown. Here, we established the interactome of the C-terminal tail region of tau and identified syntaxin 8 (STX8) as a mediator of tau release from cells. Similarly, we showed the syntaxin 6 (STX6), part of the same SNARE family as STX8 also facilitated tau release. STX6 was previously genetically linked to progressive supranuclear palsy (PSP), a tauopathy. Finally, we demonstrated that the transmembrane domain of STX6 is required and sufficient to mediate tau secretion. The differential role of STX6 and STX8 in alternative secretory pathways suggests association of tau with different secretory processes. Taken together, both syntaxins, STX6 and STX8, may contribute to AD and PSP pathogenesis by mediating release of tau from cells and facilitating pathology spreading.

scholarly journals Distinct Domains of CheA Confer Unique Functions in Chemotaxis and Cell Length in Azospirillum brasilense Sp7

2017 ◽  
Vol 199 (13) ◽  
Author(s):  
Jessica M. Gullett ◽  
Amber Bible ◽  
Gladys Alexandre
Keyword(s):  
Histidine Kinase ◽  
Azospirillum Brasilense ◽  
Molecular Mechanisms ◽  
Transmembrane Domain ◽  
Functional Divergence ◽  
Cell Length ◽  
Content Type ◽  
Evolutionary Event ◽  
Cellular Behaviors

ABSTRACT Chemotaxis is the movement of cells in response to gradients of diverse chemical cues. Motile bacteria utilize a conserved chemotaxis signal transduction system to bias their motility and navigate through a gradient. A central regulator of chemotaxis is the histidine kinase CheA. This cytoplasmic protein interacts with membrane-bound receptors, which assemble into large polar arrays, to propagate the signal. In the alphaproteobacterium Azospirillum brasilense, Che1 controls transient increases in swimming speed during chemotaxis, but it also biases the cell length at division. However, the exact underlying molecular mechanisms for Che1-dependent control of multiple cellular behaviors are not known. Here, we identify specific domains of the CheA1 histidine kinase implicated in modulating each of these functions. We show that CheA1 is produced in two isoforms: a membrane-anchored isoform produced as a fusion with a conserved seven-transmembrane domain of unknown function (TMX) at the N terminus and a soluble isoform similar to prototypical CheA. Site-directed and deletion mutagenesis combined with behavioral assays confirm the role of CheA1 in chemotaxis and implicate the TMX domain in mediating changes in cell length. Fluorescence microscopy further reveals that the membrane-anchored isoform is distributed around the cell surface while the soluble isoform localizes at the cell poles. Together, the data provide a mechanism for the role of Che1 in controlling multiple unrelated cellular behaviors via acquisition of a new domain in CheA1 and production of distinct functional isoforms. IMPORTANCE Chemotaxis provides a significant competitive advantage to bacteria in the environment, and this function has been transferred laterally multiple times, with evidence of functional divergence in different genomic contexts. The molecular principles that underlie functional diversification of chemotaxis in various genomic contexts are unknown. Here, we provide a molecular mechanism by which a single CheA protein controls two unrelated functions: chemotaxis and cell length. Acquisition of this multifunctionality is seemingly a recent evolutionary event. The findings illustrate a mechanism by which chemotaxis function may be co-opted to regulate additional cellular functions.

scholarly journals Effect of Cytoplasmic Tail Truncations on the Activity of the M2 Ion Channel of Influenza A Virus

1999 ◽  
Vol 73 (12) ◽  
pp. 9695-9701 ◽  
Author(s):  
Kurt Tobler ◽  
Marie L. Kelly ◽  
Lawrence H. Pinto ◽  
Robert A. Lamb
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Transmembrane Domain ◽  
Stop Codon ◽  
Specific Inhibitor ◽  
Cytoplasmic Tail ◽  
Proton Channel ◽  
Tail Region

ABSTRACT The M2 protein of influenza A virus forms a proton channel that is required for viral replication. The M2 ion channel is a homotetramer and has a 24-residue N-terminal extracellular domain, a 19-residue transmembrane domain, and a 54-residue cytoplasmic tail. We show here that the N-terminal methionine residue is cleaved from the mature protein. Translational stop codons were introduced into the M2 cDNA at residues 46, 52, 62, 72, 77, 82, 87, and 92. The deletion mutants were designated truncx, according to the amino acid position that was changed to a stop codon. We studied the role of the cytoplasmic tail by measuring the ion channel activity (the current sensitive to the M2-specific inhibitor amantadine) of the cytoplasmic tail truncation mutants expressed in oocytes of Xenopus laevis. When their conductance was measured over time, mutants trunc72, trunc77, and trunc92 behaved comparably to wild-type M2 protein (a decrease of only 4% over 30 min). In contrast, conductance decreased by 28% for trunc82, 27% for trunc62, and 81% for trunc52 channels. Complete closure of the channel could be observed in some cells for trunc62 and trunc52 within 30 min. These data suggest that a role of the cytoplasmic tail region of the M2 ion channel is to stabilize the pore against premature closure while the ectodomain is exposed to low pH.

scholarly journals Fragile X-associated tremor ataxia syndrome with co-occurrent progressive supranuclear palsy-like neuropathology

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Amanda N. Sacino ◽  
Stefan Prokop ◽  
Meggen A. Walsh ◽  
Jennifer Adamson ◽  
S. H. Subramony ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Patient Management ◽  
Fragile X ◽  
Brain Regions ◽  
Nuclear Inclusions ◽  
Common Phenomenon ◽  
Pathological Changes ◽  
Tau Pathology ◽  
Ataxia Syndrome ◽  
Ran Translation

Abstract Co-occurrence of multiple neuropathologic changes is a common phenomenon, most prominently seen in Alzheimer’s disease (AD) and Parkinson’s disease (PD), complicating clinical diagnosis and patient management. Reports of co-occurring pathological processes are emerging in the group of genetically defined repeat-associated non-AUG (RAN)-translation related diseases. Here we report a case of Fragile X-associated tremor-ataxia syndrome (FXTAS) with widespread and abundant nuclear inclusions of the RAN-translation related FMRpolyG-peptide. In addition, we describe prominent neuronal and glial tau pathology representing changes seen in progressive supranuclear palsy (PSP). The highest abundance of the respective pathological changes was seen in distinct brain regions indicating an incidental, rather than causal correlation.

scholarly journals Cholinergic Stress Signals Accompany MicroRNA-Associated Stereotypic Behavior and Glutamatergic Neuromodulation in the Prefrontal Cortex

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 848
Author(s):  
Gilli Moshitzky ◽  
Shai Shoham ◽  
Nimrod Madrer ◽  
Amir Mouhammed Husain ◽  
David S. Greenberg ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Motor Behavior ◽  
Brain Regions ◽  
Stereotypic Behavior ◽  
Small Rna Sequencing ◽  
Over Expression ◽  
Maze Test ◽  
Stress Signals ◽  
The Brain

Stereotypic behavior (SB) is common in emotional stress-involved psychiatric disorders and is often attributed to glutamatergic impairments, but the underlying molecular mechanisms are unknown. Given the neuro-modulatory role of acetylcholine, we sought behavioral-transcriptomic links in SB using TgR transgenic mice with impaired cholinergic transmission due to over-expression of the stress-inducible soluble ‘readthrough’ acetylcholinesterase-R splice variant AChE-R. TgR mice showed impaired organization of behavior, performance errors in a serial maze test, escape-like locomotion, intensified reaction to pilocarpine and reduced rearing in unfamiliar situations. Small-RNA sequencing revealed 36 differentially expressed (DE) microRNAs in TgR mice hippocampi, 8 of which target more than 5 cholinergic transcripts. Moreover, compared to FVB/N mice, TgR prefrontal cortices displayed individually variable changes in over 400 DE mRNA transcripts, primarily acetylcholine and glutamate-related. Furthermore, TgR brains presented c-fos over-expression in motor behavior-regulating brain regions and immune-labeled AChE-R excess in the basal ganglia, limbic brain nuclei and the brain stem, indicating a link with the observed behavioral phenotypes. Our findings demonstrate association of stress-induced SB to previously unknown microRNA-mediated perturbations of cholinergic/glutamatergic networks and underscore new therapeutic strategies for correcting stereotypic behaviors.

scholarly journals PET markers of tau and neuroinflammation are co-localized in progressive supranuclear palsy

2019 ◽  
Author(s):  
Maura Malpetti ◽  
Luca Passamonti ◽  
Timothy Rittman ◽  
P. Simon Jones ◽  
Patricia Vázquez Rodríguez ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Microglial Activation ◽  
Principal Component ◽  
Brain Regions ◽  
Clinical Severity ◽  
Binding Potential ◽  
Tau Pathology ◽  
Richardson’S Syndrome ◽  
The Relationship

AbstractBackgroundProgressive Supranuclear Palsy (PSP) is associated with tau-protein aggregation and neuroinflammation, but it remains unclear whether these pathogenic processes are related in vivo.ObjectivesWe examined the relationship between tau pathology and microglial activation using [18F]AV-1451 (indexing tau burden) and [11C]PK11195 (microglial activation) PET in n=17 patients with PSP-Richardson’s syndrome.MethodsNon-displaceable binding potential (BPND) for each ligand was quantified in 83 regions of interest (ROIs). [18F]AV-1451 and [11C]PK11195 BPND values were correlated across all ROIs. The anatomical patterns of [18F]AV-1451 and [11C]PK11195 binding co-localization was determined across sets of regions derived from principal component analyses (PCAs). Finally, PCA-derived brain patterns of tau pathology and neuroinflammation were linked to clinical severity.Results[18F]AV-1451 and [11C]PK11195 binding were positively related across all ROIs (r=0.577, p<0.0001). PCAs identified four components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [18F]AV-1451 and [11C]PK11195 components were found in sub-cortical (r=0.769, p<0.0001) and cortical components(r=0.836, p<0.0001). PCA-derived components reflecting tau burden (r=0.599, p=0.011) and neuroinflammation (r=0.713, p=0.001) in sub-cortical areas related to disease severity.ConclusionsWe show that tau pathology and neuroinflammation co-localize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine how these molecular pathologies are causally linked, we suggest that the combination of tau- and immune-oriented strategies may be useful for effective disease-modifying treatments in PSP.

scholarly journals CONTROL OF ADIPOGENIC COMMITMENT BY A STAT3-VSTM2A AXIS

2020 ◽  
Author(s):  
Manal Al Dow ◽  
Maruhen Amir Datsch Silveira ◽  
Audrée Poliquin ◽  
Laura Tribouillard ◽  
Éric Fournier ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Transmembrane Domain ◽  
Mapk Pathway ◽  
Stat3 Phosphorylation ◽  
Energy Excess ◽  
The Impact ◽  
Transcription 3 ◽  
Novel Protein

White adipose tissue (WAT) is a dynamic organ that plays crucial roles in controlling metabolic homeostasis. During development and periods of energy excess, adipose progenitors are recruited and differentiate into adipocytes to promote lipid storage capability. The identity of adipose progenitors and the signals that promote their recruitment are still incompletely characterized. We have recently identified V-set and transmembrane domain-containing protein 2A (VSTM2A) as a novel protein enriched in preadipocytes that amplifies adipogenic commitment. Despite the emerging role of VSTM2A in promoting adipogenesis, the molecular mechanisms regulating Vstm2a expression in preadipocytes are still unknown. To define the molecular mechanisms controlling Vstm2a expression, we have treated preadipocytes with an array of compounds capable of modulating established regulators of adipogenesis. Here, we report that Vstm2a expression is positively regulated by PI3K/mTOR and cAMP-dependent signaling pathways and repressed by the MAPK pathway and the glucocorticoid receptor. By integrating the impact of all the molecules tested, we identified signal transduced and activator of transcription 3 (STAT3) as a novel downstream transcription factor affecting Vstm2a expression. We show that activation of STAT3 increased Vstm2a expression, whereas its inhibition repressed this process. In mice, we found that STAT3 phosphorylation is elevated in the early phases of WAT development, an effect that strongly associates with Vstm2a expression. Our findings identify STAT3 as a key transcription factor regulating Vstm2a expression in preadipocytes.

scholarly journals α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

PLoS Biology ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. e3001287 ◽  
Author(s):  
Aysegul Dilsizoglu Senol ◽  
Maura Samarani ◽  
Sylvie Syan ◽  
Carlos M. Guardia ◽  
Takashi Nonaka ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Culture Medium ◽  
Super Resolution ◽  
Brain Regions ◽  
Tunneling Nanotubes ◽  
Donor Cells ◽  
Donor And Acceptor ◽  
Transcription Factor Eb ◽  
And Function

The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a “prion-like” manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils’ transfer to neighboring cells. We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them. These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.

scholarly journals Dynamic Changes of Cytoskeleton-Related Proteins Within Reward-Related Brain Regions in Morphine-Associated Memory

2021 ◽  
Vol 14 ◽  
Author(s):  
Xixi Yang ◽  
Yichong Wen ◽  
Yuxiang Zhang ◽  
Feifei Gao ◽  
Jingsi Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Dorsal Hippocampus ◽  
Brain Regions ◽  
Protein Activity ◽  
Dynamic Changes ◽  
Drug Induced ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Related Proteins

Drug-induced memory engages complex and dynamic processes and is coordinated at multiple reward-related brain regions. The spatiotemporal molecular mechanisms underlying different addiction phases remain unknown. We investigated the role of β-actin, as well as its potential modulatory protein activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) and extracellular signal-regulated kinase (ERK), in reward-related associative learning and memory using morphine-induced conditioned place preference (CPP) in mice. CPP was established by alternate morphine (10 mg/kg) injections and extinguished after a 10-day extinction training, while the withdrawal group failed to extinguish without training. In the nucleus accumbens (NAc), morphine enhanced the level of β-actin and Arc only during extinction, while p-ERK1/2 was increased during both CPP acquisition and extinction phases. In the dorsal hippocampus, morphine induced an upregulation of p-ERK only during extinction, while p-β-actin was elevated during both CPP establishment and extinction. In the dorsal hippocampus, Arc was elevated during CPP formation and suppressed during extinction. Compared with the NAc and dorsal hippocampus, dynamic changes in the medial prefrontal cortex (mPFC) and caudate putamen (CPu) were not very significant. These results suggested region-specific changes of p-β-actin, Arc/Arg3.1, and p-ERK1/2 protein during establishment and extinction phases of morphine-induced CPP. These findings unveiled a spatiotemporal molecular regulation in opiate-induced plasticity.

scholarly journals Gene expression in mouse brain following chronic hypoxia: role of sarcospan in glial cell death

2008 ◽  
Vol 32 (3) ◽  
pp. 370-379 ◽  
Author(s):  
Dan Zhou ◽  
Jiyi Wang ◽  
Matthew A. Zapala ◽  
Jin Xue ◽  
Nicholas J. Schork ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
High Altitude ◽  
Mouse Brain ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Brain Regions ◽  
Cortical Region ◽  
Chronic Lung Diseases

Hypoxia is a hallmark of respiratory, neurological, or hematological diseases as well as life at high altitude. For example, chronic constant hypoxia (CCH) occurs in chronic lung diseases or at high altitude, whereas chronic intermittent hypoxia (CIH) occurs in diseases such as sleep apnea or sickle cell disease. Despite the fact that such conditions are frequent, the cellular and molecular mechanisms underlying the effect of hypoxia, whether constant or intermittent, are not well understood. In this study, we first determined the effect of CCH and CIH on global gene expression in different regions of mouse brain using microarrays and then investigated the biological role of genes of interest. We found that: 1) in the cortical region, the expression level of 80 genes was significantly altered by CIH (16 up- and 64 downregulated), and this number increased to 137 genes following CCH (34 up- and 103 downregulated); 2) a similar number of gene alterations was identified in the hippocampal area, and the majority of the changes in this region were upregulations; 3) two genes (Sspn and Ttc27) were downregulated in both brain regions and following both treatments; and 4) RNA interference-mediated knockdown of Sspn increased cell death in hypoxia in a cell culture system. We conclude that CIH or CCH induced significant and distinguishable alterations in gene expression in cortex and hippocampus and that Sspn seems to play a critical role in inducing cell death under hypoxic conditions.

Trafficking of tail-anchored proteins: transport from the endoplasmic reticulum to the plasma membrane and sorting between surface domains in polarised epithelial cells

2002 ◽  
Vol 115 (8) ◽  
pp. 1689-1702 ◽  
Author(s):  
Alessandra Bulbarelli ◽  
Teresa Sprocati ◽  
Massimo Barberi ◽  
Emanuela Pedrazzini ◽  
Nica Borgese
Keyword(s):  
Plasma Membrane ◽  
Secretory Pathway ◽  
Transmembrane Domain ◽  
Mdck Cells ◽  
Apical Surface ◽  
Tail Region ◽  
Surface Distribution ◽  
C Terminus ◽  
Ta Proteins

Tail-anchored (TA) proteins, which are defined by an N-terminal cytosolic region and a C-terminal transmembrane domain (TMD), provide useful models for studying the role of the TMD in sorting within the exo-endocytic system. Previous work has shown that a short TMD is required to keep ER-resident TA proteins from escaping to downstream compartments of the secretory pathway. To investigate the role of the TMD in TA protein sorting, we used model constructs, which consisted of GFP linked at its C-terminus to the tail region of cytochrome b(5) with TMDs of differing length or hydrophobicity. Expression of these constructs in CV-1 cells demonstrated that the feature determining exit from the ER is hydrophobicity and that if exit occurs, at least a part of the protein reaches the cell surface. To investigate which pathway to the surface is followed by plasma-membrane-directed TA constructs, we expressed the TA constructs in polarised Madin Darby Canine Kidney (MDCK) cells. The constructs with 22 and 25 residue TMDs were localised basolaterally, but addition at the C-terminus of a 20-residue peptide containing an N-glycosylation site resulted in glycosylation-dependent relocation of∼50% of the protein to the apical surface. This result suggests that TA proteins may reach the basolateral surface without a signal or that our constructs contain a weak basolateral determinant that is recessive to the apical information carried by the glycan. To assess the effect of the TMDs of endogenous TA proteins, GFP was linked to the tails of syntaxin 3 and 4, which localise to the apical and basolateral surface, respectively, of MDCK cells. The two GFP fusion proteins showed a different surface distribution, which is consistent with a role for the two syntaxin TMDs in polarised sorting.

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