scholarly journals Dynamic remodeling of ribosomes and endoplasmic reticulum in axon terminals of motoneurons

2021 ◽  
Author(s):  
Chunchu Deng ◽  
Mehri Moradi ◽  
Sebastian Reinhard ◽  
Changhe Ji ◽  
Sibylle Jablonka ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Dynamic Network ◽  
Axonal Growth ◽  
Dynamic Regulation ◽  
Axon Terminals ◽  
Axon Development ◽  
Presynaptic Differentiation ◽  
Synapse Maintenance ◽  
Extracellular Stimuli ◽  
Underlying Mechanisms

In neurons, endoplasmic reticulum forms a highly dynamic network that enters axons and presynaptic terminals and plays a central role in Ca2+ homeostasis and synapse maintenance. However, the underlying mechanisms involved in regulation of its dynamic remodeling as well as its function in axon development and presynaptic differentiation remain elusive. Here, we used high resolution microscopy and live cell imaging to investigate rapid movements of endoplasmic reticulum and ribosomes in axons of cultured motoneurons after stimulation with Brain-derived neurotrophic factor. Our results indicate that the endoplasmic reticulum extends into axonal growth cone filopodia where its integrity and dynamic remodeling are regulated mainly by actin and its motor protein myosin VI. Additionally, we found that in axonal growth cones, ribosomes assemble into 80S subunits within seconds and associate with ER in response to extracellular stimuli which describes a novel function of axonal ER in dynamic regulation of local translation.

scholarly journals Dynamic remodeling of ribosomes and endoplasmic reticulum in axon terminals of motoneurons

2021 ◽  
Author(s):  
Chunchu Deng ◽  
Mehri Moradi ◽  
Sebastian Reinhard ◽  
Changhe Ji ◽  
Sibylle Jablonka ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Dynamic Network ◽  
Axonal Growth ◽  
Dynamic Regulation ◽  
Axon Terminals ◽  
Axon Development ◽  
Presynaptic Differentiation ◽  
Synapse Maintenance ◽  
Extracellular Stimuli ◽  
Underlying Mechanisms

In neurons, endoplasmic reticulum forms a highly dynamic network that enters axons and presynaptic terminals and plays a central role in Ca2+ homeostasis and synapse maintenance. However, the underlying mechanisms involved in regulation of its dynamic remodeling as well as its function in axon development and presynaptic differentiation remain elusive. Here, we used high resolution microscopy and live cell imaging to investigate rapid movements of endoplasmic reticulum and ribosomes in axons of cultured motoneurons after stimulation with Brain-derived neurotrophic factor. Our results indicate that the endoplasmic reticulum extends into axonal growth cone filopodia where its integrity and dynamic remodeling are regulated mainly by actin and its motor protein myosin VI. Additionally, we found that in axonal growth cones, ribosomes assemble into 80S subunits within seconds and associate with ER in response to extracellular stimuli which describes a novel function of axonal ER in dynamic regulation of local translation.

scholarly journals Dynamic remodeling of presynaptic endoplasmic reticulum is coordinated through actin and microtubule crosstalk and contributes to defective stimulus-response in Spinal Muscular Atrophy

2021 ◽  
Author(s):  
Michael Sendtner ◽  
Chunchu Deng ◽  
Mehri Moradi ◽  
Sebastian Reinhard ◽  
Sören Doose ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Spinal Muscular Atrophy ◽  
Axonal Degeneration ◽  
Muscular Atrophy ◽  
Dynamic Regulation ◽  
Stimulus Response ◽  
Axon Terminals ◽  
Synapse Maintenance ◽  
Extracellular Stimuli ◽  
High Resolution Microscopy

Abstract Background Axonal degeneration and defects in neuromuscular neurotransmission represent a pathological hallmark in spinal muscular atrophy (SMA) and other forms of motoneuron disease. These pathological changes do not only base on altered axonal and presynaptic architecture, but also on alterations in dynamic movements of organelles and subcellular structures that are not necessarily reflected by static histopathological changes. In neurons, a highly dynamic endoplasmic reticulum (ER) network exists in the axonal and presynaptic compartment which regulates Ca2+ homeostasis and synapse maintenance. However, the mechanisms of its dynamic regulation and mechanisms of dysfunction that contribute to neurodegeneration remain elusive. Methods Using high resolution microscopy and life imaging of cultured motoneurons from wildtype and a mouse model of spinal muscular atrophy, we investigated the dynamics of the axonal endoplasmic reticulum and ribosome distribution and activation. Results These studies revealed that the dynamic remodeling of ER in axonal filopodia of cultured motoneurons depends mainly on actin cytoskeleton. In Smn -deficient motoneurons, movements of ER in filopodia seems to be more affected than in the growth cone core. In addition, ribosome assembly that happens within seconds after exposure to Brain derived neurotrophic factors (BDNF) is reduced in axon terminals of Smn -deficient motoneurons, and also the association with ER as a response to extracellular stimuli is highly disturbed. Conclusions These findings do not only define a novel function of presynaptic ER in dynamic regulation of local translation. They also implicate impaired dynamic movements of axonal and presynaptic ER as a contributor to the pathophysiology of SMA and possibly also other neurodegenerative diseases.

scholarly journals Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 309
Author(s):  
Lijing Yang ◽  
Mengjia Hu ◽  
Yukai Lu ◽  
Songling Han ◽  
Junping Wang
Keyword(s):  
Purinergic Receptors ◽  
Therapeutic Potential ◽  
Inflammasome Activation ◽  
Hematopoietic Stem ◽  
Hematopoietic Transplantation ◽  
Proliferation And Differentiation ◽  
Extracellular Stimuli ◽  
Transplantation Complications ◽  
Underlying Mechanisms

Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.

scholarly journals Mitochondria Endoplasmic Reticulum Contact Sites (MERCs): Proximity Ligation Assay as a Tool to Study Organelle Interaction

2021 ◽  
Vol 9 ◽  
Author(s):  
Sara Benhammouda ◽  
Anjali Vishwakarma ◽  
Priya Gatti ◽  
Marc Germain
Keyword(s):  
Endoplasmic Reticulum ◽  
Fluorescence Probes ◽  
Proximity Ligation Assay ◽  
Proximity Ligation ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Endogenous Proteins ◽  
Underlying Mechanisms

Organelles cooperate with each other to regulate vital cellular homoeostatic functions. This occurs through the formation of close connections through membrane contact sites. Mitochondria-Endoplasmic-Reticulum (ER) contact sites (MERCS) are one of such contact sites that regulate numerous biological processes by controlling calcium and metabolic homeostasis. However, the extent to which contact sites shape cellular biology and the underlying mechanisms remain to be fully elucidated. A number of biochemical and imaging approaches have been established to address these questions, resulting in the identification of a number of molecular tethers between mitochondria and the ER. Among these techniques, fluorescence-based imaging is widely used, including analysing signal overlap between two organelles and more selective techniques such as in-situ proximity ligation assay (PLA). While these two techniques allow the detection of endogenous proteins, preventing some problems associated with techniques relying on overexpression (FRET, split fluorescence probes), they come with their own issues. In addition, proper image analysis is required to minimise potential artefacts associated with these methods. In this review, we discuss the protocols and outline the limitations of fluorescence-based approaches used to assess MERCs using endogenous proteins.

scholarly journals Apoptosis-Associated Speck-Like Protein Containing a CARD Deletion Ameliorates Unilateral Ureteral Obstruction Induced Renal Fibrosis and Endoplasmic Reticulum Stress in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yao Xu ◽  
Yuqing Liu ◽  
Honglei Guo ◽  
Wei Ding
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Pathological Feature ◽  
Ureter Obstruction ◽  
Underlying Mechanisms ◽  
Stage Renal Disease ◽  
End Stage

Inflammation might be one of the essential underlying mechanisms of renal fibrosis, which is considered a key pathological feature of end-stage renal disease and is closely associated with proteinuria and decreased renal function. Apoptosis-associated speck-like protein containing a CARD (ASC), identified as the central structure of inflammasome, is involved in the progression of interstitial fibrosis; however, its signal transduction pathways remain unclear. In the present study, we performed unilateral ureter obstruction (UUO) in both wild-type and ASC deletion mice to determine the contribution of ASC to renal fibrosis. Compared with control groups, UUO significantly induced renal fibrosis and collagen deposition, as evidenced by photomicrographs. ASC deletion attenuated renal injury, reduced cell infiltration and the release of inflammatory cytokines, protected against apoptosis, and downregulated the PRKR-like endoplasmic reticulum kinase (PERK) pathway of endoplasmic reticulum (ER) stress. Our data identify a novel role of ASC in the regulation of renal fibrosis and ER stress after UUO, strongly indicating that ASC could serve as an attractive target in the treatment of chronic kidney disease.

scholarly journals APOL1 risk variants cause podocytes injury through enhancing endoplasmic reticulum stress

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Hongxiu Wen ◽  
Vinod Kumar ◽  
Xiqian Lan ◽  
Seyedeh Shadafarin Marashi Shoshtari ◽  
Judith M. Eng ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Kidney Diseases ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Wild Type ◽  
Eukaryotic Translation ◽  
Risk Variants ◽  
Eukaryotic Translation Initiation ◽  
Underlying Mechanisms

Two coding sequence variants (G1 and G2) of Apolipoprotein L1 (APOL1) gene have been implicated as a higher risk factor for chronic kidney diseases (CKD) in African Americans when compared with European Americans. Previous studies have suggested that the APOL1 G1 and G2 variant proteins are more toxic to kidney cells than the wild-type APOL1 G0, but the underlying mechanisms are poorly understood. To determine whether endoplasmic reticulum (ER) stress contributes to podocyte toxicity, we generated human podocytes (HPs) that stably overexpressed APOL1 G0, G1, or G2 (Vec/HPs, G0/HPs, G1/HPs, and G2/HPs). Propidium iodide staining showed that HP overexpressing the APOL1 G1 or G2 variant exhibited a higher rate of necrosis when compared with those overexpressing the wild-type G0 counterpart. Consistently, the expression levels of nephrin and podocin proteins were significantly decreased in the G1- or G2-overexpressing cells despite the maintenance of their mRNA expressions levels. In contrast, the expression of the 78-kDa glucose-regulated protein ((GRP78), also known as the binding Ig protein, BiP) and the phosphorylation of the eukaryotic translation initiation factor 1 (eIF1) were significantly elevated in the G1/HPs and G2/HPs, suggesting a possible occurrence of ER stress in these cells. Furthermore, ER stress inhibitors not only restored nephrin protein expression, but also provided protection against necrosis in G1/HPs and G2/HPs, suggesting that APOL1 risk variants cause podocyte injury partly through enhancing ER stress.

scholarly journals Simvastatin Attenuates H2O2-Induced Endothelial Cell Dysfunction by Reducing Endoplasmic Reticulum Stress

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1782 ◽  
Author(s):  
Zhiqiang He ◽  
Xuanhong He ◽  
Menghan Liu ◽  
Lingyue Hua ◽  
Tian Wang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Umbilical Vein ◽  
Primary Role ◽  
Intracellular Cholesterol ◽  
Underlying Mechanisms ◽  
Umbilical Vein Endothelial Cells

Atherosclerosis is the pathological basis of cardiovascular disease, whilst endothelial dysfunction (ED) plays a primary role in the occurrence and development of atherosclerosis. Simvastatin has been shown to possess significant anti-atherosclerosis activity. In this study, we evaluated the protective effect of simvastatin on endothelial cells under oxidative stress and elucidated its underlying mechanisms. Simvastatin was found to attenuate H2O2-induced human umbilical vein endothelial cells (HUVECs) dysfunction and inhibit the Wnt/β-catenin pathway; however, when this pathway was activated by lithium chloride, endothelial dysfunction was clearly enhanced. Further investigation revealed that simvastatin did not alter the expression or phosphorylation of LRP6, but reduced intracellular cholesterol deposition and inhibited endoplasmic reticulum (ER) stress. Inducing ER stress with tunicamycin activated the Wnt/β-catenin pathway, whereas reducing ER stress with 4-phenylbutyric acid inhibited it. We hypothesize that simvastatin does not affect transmembrane signal transduction in the Wnt/β-catenin pathway, but inhibits ER stress by reducing intracellular cholesterol accumulation, which blocks intracellular signal transduction in the Wnt/β-catenin pathway and ameliorates endothelial dysfunction.

scholarly journals Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1617 ◽  
Author(s):  
Jin Li ◽  
Deli Zhang ◽  
Bianca J. J. M. Brundel ◽  
Marit Wiersma
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Endoplasmic Reticulum ◽  
Cardiac Disease ◽  
Healthcare Costs ◽  
Central Component ◽  
Ageing Population ◽  
Mitochondrial Stress ◽  
Underlying Mechanisms

Cardiac disease is still the leading cause of morbidity and mortality worldwide, despite some exciting and innovative improvements in clinical management. In particular, atrial fibrillation (AF) and heart failure show a steep increase in incidence and healthcare costs due to the ageing population. Although research revealed novel insights in pathways driving cardiac disease, the exact underlying mechanisms have not been uncovered so far. Emerging evidence indicates that derailed proteostasis (i.e., the homeostasis of protein expression, function and clearance) is a central component driving cardiac disease. Within proteostasis derailment, key roles for endoplasmic reticulum (ER) and mitochondrial stress have been uncovered. Here, we describe the concept of ER and mitochondrial stress and the role of interactions between the ER and mitochondria, discuss how imbalance in the interactions fuels cardiac ageing and cardiac disease (including AF), and finally assess the potential of drugs directed at conserving the interaction as an innovative therapeutic target to improve cardiac function.

scholarly journals Cholinesterase activity of lamellated sensory corpuscles in the rat lip

1986 ◽  
Vol 44 (4) ◽  
pp. 325-333 ◽  
Author(s):  
II-Sei Watanabe ◽  
Chizuka Ide
Keyword(s):  
Electron Microscopy ◽  
Endoplasmic Reticulum ◽  
Cholinesterase Activity ◽  
Light And Electron Microscopy ◽  
Reaction Products ◽  
Cell Plasma Membrane ◽  
Axon Terminals ◽  
Cell Plasma ◽  
Periaxonal Space ◽  
Lamellar Cell

Non-specific cholinesterase (ChE) activity was demonstrated in lamellated sensory corpuscles of the rat lip by light and electron microscopy using Karnovsky and Root's method. ChE activity was present in the interlamellar spaces between neighbouring lamellae as well as in the periaxonal space between axon terminals and their adjacent lamellae. Reaction products of ChE activity were also deposited in some caveolae of the lamellar cell plasma membrane, and in the cisternae of the rough endoplasmic reticulum as well as in the nuclear envelope of lamellar cell bodies. No definite reaction products were detected within the axon terminals. These findings show that the lamellated corpuscles in the rat lip, like other mechanoreceptors, have an intense ChE activity which is mainly associated with lamellar cells. It can be said that ChE histochemistry is useful to detect mechanoreceptors. The functional significance of ChE in mechanoreceptors is discussed.

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