scholarly journals Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo

2017 ◽  
Vol 114 (43) ◽  
pp. E9153-E9162 ◽  
Author(s):  
Amy L. Herbert ◽  
Meng-meng Fu ◽  
Catherine M. Drerup ◽  
Ryan S. Gray ◽  
Breanne L. Harty ◽  
...  
Keyword(s):  
Action Potentials ◽  
Animal Studies ◽  
Mrna Transport ◽  
Anterograde Transport ◽  
Protein Levels ◽  
Motor Complex ◽  
Mrna Granules ◽  
The Central Nervous System ◽  
Dynactin Complex

Oligodendrocytes in the central nervous system produce myelin, a lipid-rich, multilamellar sheath that surrounds axons and promotes the rapid propagation of action potentials. A critical component of myelin is myelin basic protein (MBP), expression of which requires anterograde mRNA transport followed by local translation at the developing myelin sheath. Although the anterograde motor kinesin KIF1B is involved in mbp mRNA transport in zebrafish, it is not entirely clear how mbp transport is regulated. From a forward genetic screen for myelination defects in zebrafish, we identified a mutation in actr10, which encodes the Arp11 subunit of dynactin, a critical activator of the retrograde motor dynein. Both the actr10 mutation and pharmacological dynein inhibition in zebrafish result in failure to properly distribute mbp mRNA in oligodendrocytes, indicating a paradoxical role for the retrograde dynein/dynactin complex in anterograde mbp mRNA transport. To address the molecular mechanism underlying this observation, we biochemically isolated reporter-tagged Mbp mRNA granules from primary cultured mammalian oligodendrocytes to show that they indeed associate with the retrograde motor complex. Next, we used live-cell imaging to show that acute pharmacological dynein inhibition quickly arrests Mbp mRNA transport in both directions. Chronic pharmacological dynein inhibition also abrogates Mbp mRNA distribution and dramatically decreases MBP protein levels. Thus, these cell culture and whole animal studies demonstrate a role for the retrograde dynein/dynactin motor complex in anterograde mbp mRNA transport and myelination in vivo.

scholarly journals Dynactin Is Required for Coordinated Bidirectional Motility, but Not for Dynein Membrane Attachment

2007 ◽  
Vol 18 (6) ◽  
pp. 2081-2089 ◽  
Author(s):  
Marjan Haghnia ◽  
Valeria Cavalli ◽  
Sameer B. Shah ◽  
Kristina Schimmelpfeng ◽  
Richard Brusch ◽  
...  
Keyword(s):  
Molecular Motor ◽  
Retrograde Transport ◽  
Anterograde Transport ◽  
Membrane Attachment ◽  
Membrane Compartments ◽  
Human Motor ◽  
Neuronal Vesicles ◽  
Dynactin Complex ◽  
Lateral Sclerosis

Transport of cellular and neuronal vesicles, organelles, and other particles along microtubules requires the molecular motor protein dynein ( Mallik and Gross, 2004 ). Critical to dynein function is dynactin, a multiprotein complex commonly thought to be required for dynein attachment to membrane compartments ( Karki and Holzbaur, 1999 ). Recent work also has found that mutations in dynactin can cause the human motor neuron disease amyotrophic lateral sclerosis ( Puls et al., 2003 ). Thus, it is essential to understand the in vivo function of dynactin. To test directly and rigorously the hypothesis that dynactin is required to attach dynein to membranes, we used both a Drosophila mutant and RNA interference to generate organisms and cells lacking the critical dynactin subunit, actin-related protein 1. Contrary to expectation, we found that apparently normal amounts of dynein associate with membrane compartments in the absence of a fully assembled dynactin complex. In addition, anterograde and retrograde organelle movement in dynactin deficient axons was completely disrupted, resulting in substantial changes in vesicle kinematic properties. Although effects on retrograde transport are predicted by the proposed function of dynactin as a regulator of dynein processivity, the additional effects we observed on anterograde transport also suggest potential roles for dynactin in mediating kinesin-driven transport and in coordinating the activity of opposing motors ( King and Schroer, 2000 ).

scholarly journals RUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning

2021 ◽  
Author(s):  
Gaurav Kumar ◽  
Prateek Chawla ◽  
Sanya Chadha ◽  
Sheetal Sharma ◽  
Kanupriya Sethi ◽  
...  
Keyword(s):  
G Protein ◽  
Spatial Organization ◽  
Adaptor Protein ◽  
Retrograde Transport ◽  
Anterograde Transport ◽  
Motor Complex ◽  
Gtp Binding ◽  
Microtubule Motor ◽  
Mobile Fraction ◽  
Dynactin Complex

Abstract The whole-cell scale spatial organization of lysosomes is regulated by their bidirectional motility on microtubule tracks. Small GTP-binding (G) protein, Arl8b, stimulates the anterograde transport of lysosomes by recruiting adaptor protein SKIP (also known as PLEKHM2), which in turn couples the microtubule motor kinesin-1. Here, we have identified an Arl8b effector, RUN and FYVE domain-containing protein family member 3, RUFY3, which drives the retrograde transport of lysosomes. Artificial targeting of RUFY3 to the surface of mitochondria was sufficient to drive their perinuclear positioning. We find that RUFY3 interacts with the JIP4-Dynein-Dynactin complex and mediates Arl8b association with the retrograde motor complex. The mobile fraction of the total lysosomes per cell was significantly enhanced upon RUFY3 depletion, suggesting that RUFY3 maintains the lysosomes clustering within the perinuclear cloud. Expectedly, RUFY3 knockdown disrupted the perinuclear positioning of lysosomes upon nutrient starvation and/or serum depletion, although lysosome continued to undergo fusion with autophagosomes. Interestingly, lysosome fission events were more frequent in RUFY3-depleted cells and accordingly, there was a striking reduction in lysosome size, an effect that was also observed in dynein and JIP4 depleted cells. These findings indicate that the dynein-dependent “perinuclear cloud” arrangement of lysosomes also regulates the size of these proteolytic compartments and, likely, their cellular roles.

scholarly journals New Evidence on the Role of D-Aspartate Metabolism in Regulating Brain and Endocrine System Physiology: From Preclinical Observations to Clinical Applications

2020 ◽  
Vol 21 (22) ◽  
pp. 8718
Author(s):  
Alessandro Usiello ◽  
Maria Maddalena Di Fiore ◽  
Arianna De Rosa ◽  
Sara Falvo ◽  
Francesco Errico ◽  
...  
Keyword(s):  
Animal Studies ◽  
Endocrine System ◽  
Postnatal Life ◽  
Functional Development ◽  
The Central Nervous System ◽  
High Concentrations ◽  
System Physiology ◽  
Metabolizing Enzyme

The endogenous amino acids serine and aspartate occur at high concentrations in free D-form in mammalian organs, including the central nervous system and endocrine glands. D-serine (D-Ser) is largely localized in the forebrain structures throughout pre and postnatal life. Pharmacologically, D-Ser plays a functional role by acting as an endogenous coagonist at N-methyl-D-aspartate receptors (NMDARs). Less is known about the role of free D-aspartate (D-Asp) in mammals. Notably, D-Asp has a specific temporal pattern of occurrence. In fact, free D-Asp is abundant during prenatal life and decreases greatly after birth in concomitance with the postnatal onset of D-Asp oxidase expression, which is the only enzyme known to control endogenous levels of this molecule. Conversely, in the endocrine system, D-Asp concentrations enhance after birth during its functional development, thereby suggesting an involvement of the amino acid in the regulation of hormone biosynthesis. The substantial binding affinity for the NMDAR glutamate site has led us to investigate the in vivo implications of D-Asp on NMDAR-mediated responses. Herein we review the physiological function of free D-Asp and of its metabolizing enzyme in regulating the functions of the brain and of the neuroendocrine system based on recent genetic and pharmacological human and animal studies.

scholarly journals Not merely a protective packing organ? A review of fascia and its force transmission capacity

2018 ◽  
Vol 124 (1) ◽  
pp. 234-244 ◽  
Author(s):  
Jan Wilke ◽  
Robert Schleip ◽  
Can A. Yucesoy ◽  
Winfried Banzer
Keyword(s):  
Animal Studies ◽  
Biomechanical Properties ◽  
Force Transmission ◽  
Locomotor System ◽  
Myofascial Force Transmission ◽  
Transmitted Force ◽  
Muscle Fascia ◽  
The Central Nervous System

Recent research indicates that fascia is capable of changing its biomechanical properties. Moreover, as it links the skeletal muscles, forming a body-wide network of multidirectional myofascial continuity, the classical conception of muscles as independent actuators has been challenged. Hence, the present synthesis review aims to characterize the mechanical relevance of the connective tissue for the locomotor system. Results of cadaveric and animal studies suggest a clinically relevant myofascial force transmission to neighboring structures within one limb (e.g., between synergists) and in the course of muscle-fascia chains (e.g., between leg and trunk). Initial in vivo trials appear to underpin these findings, demonstrating the existence of nonlocal exercise effects. However, the factors influencing the amount of transmitted force (e.g., age and physical activity) remain controversial, as well as the role of the central nervous system within the context of the observed remote exercise effects.

scholarly journals PDK1 is a negative regulator of axon regeneration

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Hyemin Kim ◽  
Jinyoung Lee ◽  
Yongcheol Cho
Keyword(s):  
Nervous System ◽  
Axon Regeneration ◽  
Dorsal Root Ganglion Neurons ◽  
Negative Regulator ◽  
Protein Levels ◽  
Adult Mice ◽  
The Central Nervous System ◽  
Ganglion Neurons

AbstractAxon regeneration in the central nervous system is inefficient. However, the neurons in the peripheral nervous system display robust regeneration after injury, indicating that axonal regeneration is differentially controlled under various conditions. To identify those molecules regulating axon regeneration, comparative analysis from dorsal root ganglion neurons at embryonic or adult stages is utilized, which reveals that PDK1 is functions as a negative regulator of axon regeneration. PDK1 is downregulated in embryonic neurons after axotomy. In contrast, sciatic nerve axotomy upregulated PDK1 at protein levels from adult mice. The knockdown of PDK1 or the chemical inhibition of PDK1 promotes axon regeneration in vitro and in vivo. Here we present PDK1 as a new player to negatively regulate axon regeneration and as a potential target in the development of therapeutic applications.

scholarly journals Defining and predicting transdiagnostic categories of neurodegenerative disease

2019 ◽  
Author(s):  
Eli J. Cornblath ◽  
John L. Robinson ◽  
Virginia M.-Y. Lee ◽  
John Q. Trojanowski ◽  
Danielle S. Bassett
Keyword(s):  
Neurodegenerative Disease ◽  
Clinical Neurology ◽  
Disease Clusters ◽  
Cluster Membership ◽  
Protein Levels ◽  
Overlapping Data ◽  
The Central Nervous System ◽  
Disease Subtypes ◽  
Neuropathological Evaluation

In current models of neurodegeneration, individual diseases are defined by the presence of one or two pathogenic protein species. Yet, it is the rule rather than the exception that a patient meets criteria for more than one disease. This fact often remains hidden until autopsy, when neuropathological evaluation can assign disease labels based on gold-standard criteria. Ultimately, the prevalence of concomitant diagnoses and the inability to infer an underlying neuropathological syndrome from clinical variables hinders the identification of patients who might be good candidates for a particular intervention. Here, by applying graph-based clustering to post-mortem histopathological data from 1389 patients with degeneration in the central nervous system, we generate 4 non-overlapping, data-driven disease categories that simultaneously account for amyloid-β plaques, tau neurofibrillary tangles, α-synuclein inclusions, neuritic plaques, TDP-43 inclusions, angiopathy, neuron loss, and gliosis. The resulting disease clusters are transdiagnostic in the sense that each cluster contains patients belonging to multiple different existing disease diagnoses, who colocalize in clusters according to the pathogenic protein aggregates known to drive each disease. We show that our disease clusters, defined solely by histopathology, separate patients in terms of cognitive phenotypes, cerebrospinal fluid (CSF) protein levels, and genotype in a manner that is not trivially explained by the representation of individual diseases within each cluster. Finally, we use cross-validated multiple logistic regression to generate high accuracy predictions (AUC > 0.9) of membership to both existing disease categories and transdiagnostic clusters based on CSF protein levels and genotype, both accessible in vivo. Broadly, our approach parses phenotypic and genotypic heterogeneity in neurodegenerative disease, and represents a general framework for identifying otherwise-fuzzy disease subtypes in other areas of medicine, such as epilepsy, vascular disease, and cancer. In clinical neurology, the statistical models we generate may be useful for repurposing drugs by comparing efficacy to probabilistic estimates of disease cluster membership, as well as for future trials that could be targeted towards an algorithmically defined family of diseases.

scholarly journals Glial contribution to cyclodextrin-mediated reversal of cholesterol accumulation in murine NPC1-deficient neurons in vivo

2021 ◽  
Author(s):  
Amélie Barthelemy ◽  
Valérie Demais ◽  
Izabela-Cristina Stancu ◽  
Eugeniu Vasile ◽  
Tom Houben ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glial Cells ◽  
Animal Studies ◽  
Lysosomal Storage ◽  
Genes Encoding ◽  
The Central Nervous System ◽  
Lysosomal System ◽  
Niemann Pick

AbstractNiemann-Pick type C (NPC) disease is a rare and fatal lysosomal storage disorder presenting severe neurovisceral symptoms. Disease-causing mutations in genes encoding either NPC1 or NPC2 protein provoke accumulation of cholesterol and other lipids in specific structures of the endosomal-lysosomal system and degeneration of specific cells, notably neurons in the central nervous system (CNS). 2-hydroxypropyl-beta-cyclodextrin (CD) emerged as potential therapeutic approach based on animal studies and clinical data, but the mechanism of action on neurons has remained unclear. To address this topic in vivo, we took advantage of the retina as highly accessible part of the (CNS) and intravitreal injections as mode of drug administration. We find that CD enters the endosomal-lysosomal system of neurons and enables the release of lipid-laden lamellar inclusions, which are then removed from the extracellular space by specific types of glial cells. Thus, CD triggers a concerted action of neurons and glial cells to restore lipid homeostasis in the central nervous system.

Effect of brefeldin A (BFA) on the unique surface coat of pulmonary intravascular macrophages (PIMs) of sheep: Ultrastructural and cytochemical study

1993 ◽  
Vol 51 ◽  
pp. 18-19
Author(s):  
Baljit Singh
Keyword(s):  
Brefeldin A ◽  
Ultrastructural Feature ◽  
Surface Coat ◽  
Anterograde Transport ◽  
Cytochemical Study ◽  
Active Involvement ◽  
Electron Lucent ◽  
Pulmonary Intravascular Macrophages ◽  
Unique Surface

The PIM of sheep, calf, goat and horse has a characteristic ultrastructural feature in the form of a unique, heparin sensitive, globular surface coat present around the plasma membrane with an intervening electron lucent space of 32-40 nm. We previously showed the active involvement of this surface coat in the phagocytosis of tracer material like monastral blue and cationized ferritin. The surface coat is capable of reconstitution in vivo following disruption with heparin. The present study was aimed to investigate whether PIM is the source of surface coat or not. In the recent years the BFA has been extensively used to understand the secretory pathways in the cells because of its ability to cause a rapid and reversible block to the anterograde transport of proteins from the endoplasmic reticulum to the Golgi.Sheep (n=6) were weighed, their plasma volume was calculated indirectly and based on which a sufficient single intravenous dose of BFA was given so as to reach a concentration of 4-5 microgram/ml of plasma.

Decellularized bone extracellular matrix in skeletal tissue engineering

2020 ◽  
Vol 48 (3) ◽  
pp. 755-764
Author(s):  
Benjamin B. Rothrauff ◽  
Rocky S. Tuan
Keyword(s):  
Tissue Engineering ◽  
Bone Regeneration ◽  
Tissue Regeneration ◽  
Animal Studies ◽  
Tumor Resection ◽  
Regenerative Capacity ◽  
Skeletal Tissue ◽  
Large Bone

Bone possesses an intrinsic regenerative capacity, which can be compromised by aging, disease, trauma, and iatrogenesis (e.g. tumor resection, pharmacological). At present, autografts and allografts are the principal biological treatments available to replace large bone segments, but both entail several limitations that reduce wider use and consistent success. The use of decellularized extracellular matrices (ECM), often derived from xenogeneic sources, has been shown to favorably influence the immune response to injury and promote site-appropriate tissue regeneration. Decellularized bone ECM (dbECM), utilized in several forms — whole organ, particles, hydrogels — has shown promise in both in vitro and in vivo animal studies to promote osteogenic differentiation of stem/progenitor cells and enhance bone regeneration. However, dbECM has yet to be investigated in clinical studies, which are needed to determine the relative efficacy of this emerging biomaterial as compared with established treatments. This mini-review highlights the recent exploration of dbECM as a biomaterial for skeletal tissue engineering and considers modifications on its future use to more consistently promote bone regeneration.

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