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.

The role of the cerebellum in creativity and expert stone knapping

2020 ◽  
pp. 105971232096646
Author(s):  
Frederick L Coolidge
Keyword(s):  
Critical Role ◽  
Brain Regions ◽  
Stone Tool ◽  
Fine Motor ◽  
Engagement Theory ◽  
Motor Movements ◽  
And Function ◽  
The Mind ◽  
Stone Knapping

The purpose of this article is to review the evolution and function of the cerebellum, particularly in regard to its role in creativity and expert stone knapping. First, the article reviews the history of the cerebellum, its evolution and phylogenetics, and its concerted evolution with various brain regions. It also notes the critical role of the cerebellum and the cerebro-cerebellar network in its traditionally recognized control of gross and fine motor movements and in its exaptation for basic and higher level cognitive processes, particularly in regard to increasingly more sophisticated stone knapping. Also, reviewed are various theories, advanced over the past three decades, of how the cerebellum tweaks and refines thoughts, images, and ideas just as it refines and smooths motor movements. Baddeley’s working memory model is also prominently featured, as are the works of Ito, Vandervert, and others on the cerebellum’s role in novel problem-solving, insight, and creativity. Finally, this article reviews two “Cognitive Rubicons” in stone tool knapping, Theory of Mind and stone knapping, and Malafouris’ Material Engagement Theory. The article concludes with a novel hypothesis that the automaticity provided by the cerebellum derived from extensive practice in stone knapping may have freed Baddeley’s central executive from its attentional demands and allows the mind to “wander and wonder.”

scholarly journals Ca2+ signaling evoked by activation of Na+ channels and Na+/Ca2+ exchangers is required for GABA-induced NG2 cell migration

2009 ◽  
Vol 186 (1) ◽  
pp. 113-128 ◽  
Author(s):  
Xiao-ping Tong ◽  
Xiang-yao Li ◽  
Bing Zhou ◽  
Wanhua Shen ◽  
Zhi-jun Zhang ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Physiological Role ◽  
Brain Regions ◽  
Na Channels ◽  
Typical Action ◽  
Sequential Activation ◽  
Ng2 Cells ◽  
And Function ◽  
Ca2 Channels

NG2 cells originate from various brain regions and migrate to their destinations during early development. These cells express voltage-gated Na+ channels but fail to produce typical action potentials. The physiological role of Na+ channels in these cells is unclear. We found that GABA induces membrane depolarization and Ca2+ elevation in NG2 cells, a process requiring activation of GABAA receptors, Na+ channels, and Na+/Ca2+ exchangers (NCXs), but not Ca2+ channels. We have identified a persistent Na+ current in these cells that may underlie the GABA-induced pathway of prolonged Na+ elevation, which in turn triggers Ca2+ influx via NCXs. This unique Ca2+ signaling pathway is further shown to be involved in the migration of NG2 cells. Thus, GABAergic signaling mediated by sequential activation of GABAA receptors, noninactivating Na+ channels, and NCXs may play an important role in the development and function of NG2 glial cells in the brain.

SEM Observation of Composite Ceramic Scaffolds’ Surface during Incubation in Culture Medium with or without Human PDL Fibroblasts

2011 ◽  
Vol 493-494 ◽  
pp. 866-871
Author(s):  
Anna Theocharidou ◽  
K. Tsoptsias ◽  
Eleana Kontonasaki ◽  
Lambrini Papadopoulou ◽  
C. Panayiotou ◽  
...  
Keyword(s):  
Culture Medium ◽  
Cell Attachment ◽  
Surface Characteristics ◽  
Composite Ceramic ◽  
Surface Porosity ◽  
Periodontal Ligament Fibroblasts ◽  
Eds Analysis ◽  
Before And After ◽  
And Function

Chitin is a polysaccharide abundant in nature. Its’ deacetylation product-chitosan- in combination with gelatin (collagen product) is commonly used asbiopolymer scaffold for tissue engineering. The aim of this study was to investigate diffrerences in surface characteristics of chitin (CHN CCS) and chitosan –gelatin (CHS-G CCS) composite ceramic scaffolds (CCS), during their incubation in culture medium (DMEM) with or without human periodontal ligament fibroblasts (HPDLF). CHN CCS and CHS- G CCS, with pore size 70-200μm, were fabricated on the surface of ceramic disks, being coated with a mixture of bioactive glass – ceramic (1:1 wt). Three CCSs of each type were constructed. Each CCS was incubated at 37 °C up to 10 days, either only in DMEM supplemented with 10% FCS or in DMEM with the presence of 105HPDLF. SEM microphotographs and EDS analysis, before and after incubation, were used to investigate CCSs’ surface alterations. Before incubation, all type of CCSs appeared to be macro porous with high interconnectivity. Exposed to incubation, CHN CCSs’ surface porosity seemed to be rapidly reduced and a rough surface without pores was observed with or without HPDLF. Attached HPDLF were rarely detected. CHS-G CCSs appeared to retain surface porosity in DMEM without cells. In HPDLF culture an almost uniform surface with organic aggregates and attached cells was observed. Until day 10, HPDLF could only be detected at CHS-G CCS’s surface. Conclusion: SEM microphotographs observations indicate that CHN CCSs’ incubation in DMEM led in early and rapid coalescence of surface pores, thus inhibiting HPDLF attachment. HPDLF attachment on CHS-G CCSs confirm the beneficial role of gelatin, while differences in CHS-G CCSs’ surface with and without HPDLF culture indicate that not only sedimentation of medium's ingredients, but cell attachment and function could decrease surface’s porosity, affecting consequently HPDLF proliferation.

Relationship between Adaptive Changing of Lysophosphatidylethanolamine Content in the Bacterial Envelope and Ampicillin Sensitivity of Yersinia pseudotuberculosis

2018 ◽  
Vol 28 (5) ◽  
pp. 236-239
Author(s):  
Nina Sanina ◽  
Lyudmila Pomazenkova ◽  
Svetlana Bakholdina ◽  
Natalia Chopenko ◽  
Anna Zabolotnaya ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Culture Medium ◽  
Bacterial Resistance ◽  
Yersinia Pseudotuberculosis ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Control Value ◽  
And Function

The low permeability of porin channels is the possible reason for Gram-negative bacterial resistance to antibiotics. The adaptive accumulation of lysophosphatidylethanolamine (LPE) in <i>Yersinia pseudotuberculosis</i> induces conformational changes of OmpF porin that may hinder the transport of antibiotics through this channel. The present study was aimed to test whether the changes in LPE content affect the resistance of bacteria to ampicillin. The addition of glucose to the culture medium was shown to simultaneously increase the level of LPE and minimum inhibitory concentration (MIC) for ampicillin of <i>Y. pseudotuberculosis</i> cells 6- and 2-fold, respectively. However, the coadministration of glucose and polyphenol extract from buckwheat husks reduced the content of LPE 2-fold and restored MIC to the control value. Thus, PBEH can be used as antibiotic adjuvant to improve an antibiotic’s ability to cross the outer membrane. The present work demonstrated: (i) the role of adaptive changes in the lipid composition of <i>Y. pseudotuberculosis</i> in<i></i> the development of antibiotic resistance, and (ii) the promising use of PBEH in combination therapy to increase the susceptibility of Gram-negative bacteria to the conventional β-lactam antibiotics, probably attenuating in vivo a previously demonstrated effect of LPE on the conformation and function of the OmpF channel.

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 Translation Inhibitors Activate Autophagy Master Regulators TFEB and TFE3

2021 ◽  
Vol 22 (21) ◽  
pp. 12083
Author(s):  
Thao Thi Dang ◽  
Sung Hoon Back
Keyword(s):  
Transcription Factor ◽  
Nuclear Translocation ◽  
Degradation Pathway ◽  
Major Protein ◽  
Translation Inhibition ◽  
Growth Factor Deprivation ◽  
Transcription Factor Eb ◽  
Cellular Stresses ◽  
And Function

The autophagy-lysosome pathway is a major protein degradation pathway stimulated by multiple cellular stresses, including nutrient or growth factor deprivation, hypoxia, misfolded proteins, damaged organelles, and intracellular pathogens. Recent studies have revealed that transcription factor EB (TFEB) and transcription factor E3 (TFE3) play a pivotal role in the biogenesis and functions of autophagosome and lysosome. Here we report that three translation inhibitors (cycloheximide, lactimidomycin, and rocaglamide A) can facilitate the nuclear translocation of TFEB/TFE3 via dephosphorylation and 14-3-3 dissociation. In addition, the inhibitor-mediated TFEB/TFE3 nuclear translocation significantly increases the transcriptional expression of their downstream genes involved in the biogenesis and function of autophagosome and lysosome. Furthermore, we demonstrated that translation inhibition increased autophagosome biogenesis but impaired the degradative autolysosome formation because of lysosomal dysfunction. These results highlight the previously unrecognized function of the translation inhibitors as activators of TFEB/TFE3, suggesting a novel biological role of translation inhibition in autophagy regulation.

scholarly journals Intricate structure of the interphase chromocenter revealed by the analysis of a factor involved in species formation

2018 ◽  
Author(s):  
Natalia Y. Kochanova ◽  
Tamas Schauer ◽  
Grusha Primal Mathias ◽  
Andrea Lukacs ◽  
Andreas Schmidt ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Super Resolution ◽  
Pericentric Heterochromatin ◽  
Gene Encoding ◽  
Centromeric Chromatin ◽  
Species Formation ◽  
Higher Eukaryotes ◽  
And Function ◽  
Super Resolution Microscopy

ABSTRACTIn higher eukaryotes centromeres often coalesce into a large intranuclear domain called the chromocenter. Chromocenters are important for the organization of pericentric heterochromatin and a disturbance of their formation results in an upregulation of repetitive elements and causes defects in chromosome segregation. Mutations in the gene encoding for the centromere associated Drosophila speciation factor HMR show very similar phenotypes suggesting a role of HMR in chromocenter architecture and function. We performed confocal and super resolution microscopy as well as proximity based biotinylation experiments of HMR and its associated protein HP1a to generate a molecular map of HMR and HP1a bound chromatin. Our work reveals an intricate internal structure of the centromeric chromatin region, which suggests a role of HMR in separating heterochromatin from centromeric chromatin.

Scanning electron microscopic study of collagen fibrillogenesis and extracellular compartmentalization in the chick embryo tendon

1986 ◽  
Vol 44 ◽  
pp. 208-209
Author(s):  
Grace C.H. Yang
Keyword(s):  
Chick Embryo ◽  
Extracellular Space ◽  
Fibroblast Cell ◽  
Collagen Fibrils ◽  
Electron Microscopic ◽  
Voltage Electron ◽  
Scanning Electron Microscopic Study ◽  
Microscopic Studies ◽  
And Function

The size and organization of collagen fibrils in the extracellular matrix is an important determinant of tissue structure and function. The synthesis and deposition of collagen involves multiple steps which begin within the cell and continue in the extracellular space. High-voltage electron microscopic studies of the chick embryo cornea and tendon suggested that the extracellular space is compartmentalized by the fibroblasts for the regulation of collagen fibril, bundle, and tissue specific macroaggregate formation. The purpose of this study is to gather direct evidence regarding the association of the fibroblast cell surface with newly formed collagen fibrils, and to define the role of the fibroblast in the control and the precise positioning of collagen fibrils, bundles, and macroaggregates during chick tendon development.

Role of the Cilia Membrane in Control of Microtubule Sliding

1980 ◽  
Vol 38 ◽  
pp. 612-615
Author(s):  
Edna S. Kaneshiro
Keyword(s):  
Control Mechanism ◽  
Beat Frequency ◽  
Surface Membrane ◽  
Ciliary Membrane ◽  
Ciliary Beating ◽  
Ciliary Reversal ◽  
Voltage Dependent ◽  
Reversal Mechanism ◽  
And Function

It is currently believed that ciliary beating results from microtubule sliding which is restricted in regions to cause bending. Cilia beat can be modified to bring about changes in beat frequency, cessation of beat and reversal in beat direction. In ciliated protozoans these modifications which determine swimming behavior have been shown to be related to intracellular (intraciliary) Ca2+ concentrations. The Ca2+ levels are in turn governed by the surface ciliary membrane which exhibits increased Ca2+ conductance (permeability) in response to depolarization. Mutants with altered behaviors have been isolated. Pawn mutants fail to exhibit reversal of the effective stroke of ciliary beat and therefore cannot swim backward. They lack the increased inward Ca2+ current in response to depolarizing stimuli. Both normal and pawn Paramecium made leaky to Ca2+ by Triton extrac¬tion of the surface membrane exhibit backward swimming only in reactivating solutions containing greater than IO-6 M Ca2+ Thus in pawns the ciliary reversal mechanism itself is left operational and only the control mechanism at the membrane is affected. The topographic location of voltage-dependent Ca2+ channels has been identified as a component of the ciliary mem¬brane since the inward Ca2+ conductance response is eliminated by deciliation and the return of the response occurs during cilia regeneration. Since the ciliary membrane has been impli¬cated in the control of Ca2+ levels in the cilium and therefore is the site of at least one kind of control of microtubule sliding, we have focused our attention on understanding the structure and function of the membrane.

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