Journal articles on the topic 'Axonal transport'
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1
Miller, Kyle E., and Michael P. Sheetz. "Direct evidence for coherent low velocity axonal transport of mitochondria." Journal of Cell Biology 173, no. 3 (May 8, 2006): 373–81. http://dx.doi.org/10.1083/jcb.200510097.
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Axonal growth depends on axonal transport. We report the first global analysis of mitochondrial transport during axonal growth and pauses. In the proximal axon, we found that docked mitochondria attached to the cytoskeletal framework that were stationary relative to the substrate and fast axonal transport fully accounted for mitochondrial transport. In the distal axon, we found both fast mitochondrial transport and a coherent slow transport of the mitochondria docked to the axonal framework (low velocity transport [LVT]). LVT was distinct from previously described transport processes; it was coupled with stretching of the axonal framework and, surprisingly, was independent of growth cone advance. Fast mitochondrial transport decreased and LVT increased in a proximodistal gradient along the axon, but together they generated a constant mitochondrial flux. These findings suggest that the viscoelastic stretching/creep of axons caused by tension exerted by the growth cone, with or without advance, is seen as LVT that is followed by compensatory intercalated addition of new mitochondria by fast axonal transport.
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Spinner, Michael A., Katherine Pinter, Catherine M. Drerup, and Tory G. Herman. "A Conserved Role for Vezatin Proteins in Cargo-Specific Regulation of Retrograde Axonal Transport." Genetics 216, no. 2 (August 11, 2020): 431–45. http://dx.doi.org/10.1534/genetics.120.303499.
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Active transport of organelles within axons is critical for neuronal health. Retrograde axonal transport, in particular, relays neurotrophic signals received by axon terminals to the nucleus and circulates new material among en passant synapses. A single motor protein complex, cytoplasmic dynein, is responsible for nearly all retrograde transport within axons: its linkage to and transport of diverse cargos is achieved by cargo-specific regulators. Here, we identify Vezatin as a conserved regulator of retrograde axonal transport. Vertebrate Vezatin (Vezt) is required for the maturation and maintenance of cell-cell junctions and has not previously been implicated in axonal transport. However, a related fungal protein, VezA, has been shown to regulate retrograde transport of endosomes in hyphae. In a forward genetic screen, we identified a loss-of-function mutation in the Drosophila vezatin-like (vezl) gene. We here show that vezl loss prevents a subset of endosomes, including signaling endosomes containing activated BMP receptors, from initiating transport out of motor neuron terminal boutons. vezl loss also decreases the transport of endosomes and dense core vesicles, but not mitochondria, within axon shafts. We disrupted vezt in zebrafish and found that vezt loss specifically impairs the retrograde axonal transport of late endosomes, causing their accumulation in axon terminals. Our work establishes a conserved, cargo-specific role for Vezatin proteins in retrograde axonal transport.
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KUZNETSOV, A. V., A. A. AVRAMENKO, and D. G. BLINOV. "MODELING TRAFFIC JAMS IN SLOW AXONAL TRANSPORT." Journal of Mechanics in Medicine and Biology 10, no. 03 (September 2010): 445–65. http://dx.doi.org/10.1142/s0219519410003502.
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The purpose of this paper is to develop a model capable of simulating traffic jams in slow axonal transport. Slowing of slow axonal transport is an early sign of some neurodegenerative diseases. Axonal swellings observed near the end stage of such diseases may be an indication of traffic jams developing in axons that cause the slowing down of slow axonal transport. Traffic jams may result from misregulation of microtubule-associated proteins caused by an imbalance in intracellular signaling or by mutations of these proteins. This misregulation leads to a decay of microtubule tracks in axons, effectively reducing the number of "railway tracks" available for molecular-motor-assisted transport of intracellular organelles. In this paper, the decay of microtubule tracks is modeled by a reduction of the number density of microtubules in the central part of the axon. Simulation results indicate that the model predicts the build-up of the bell-shaped concentration wave, as the wave approaches the bottleneck (blockage) region. This increase in concentration will likely plug the bottleneck region resulting in a traffic jam that would hinder the slow axonal transport.
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Mehta, Arpan, Bhuvaneish Selvaraj, Owen Dando, Karen Burr, Giles Hardingham, and Siddharthan Chandran. "229 Dysregulated axonal homeostasis in C9orf72 iPSC-derived motor neurones." Journal of Neurology, Neurosurgery & Psychiatry 90, no. 12 (November 14, 2019): e57.3-e57. http://dx.doi.org/10.1136/jnnp-2019-abn-2.193.
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Dysregulated axonal homeostasis is a potential pathomechanism in ALS, but its relevance to the commonest known genetic mutation in ALS – the C9orf72 repeat expansion – remains unclear. We performed unbiased transcriptomics of cell-autonomous C9orf72 motor neurone (MN) perturbations in a humanised model using patient-derived induced pluripotent stem-cell lines against an isogenic background generated by CRISPR/Cas9 and studied the functional consequences of downstream axonal hits. Differential gene expression analysis examined the intersection in differentially expressed genes between the mutant-isogene pairs, revealing 215 genes: 95 up and 120 down. Pathway analysis showed an axonal signature, with upregulation of pathways involved in cytoskeletal organisation, axon guidance, and Trk receptor signalling, and downregulation of pathways involved in the mitochondrial electron transport chain and axon guidance. Significantly dysregulated genes were confirmed using real-time quantitative PCR. This led to two hypotheses examining for aberrations in axonal length and transport. Axonal length was measured using manual tracking of SMI-312 labelled axons. Axonal transport was determined by tracking Ds-Red2 labelled mitochondrial movement using a live-imaging setup and analysed using KymoToolBox. Both axonal length and transport were reduced in the mutants compared to their isogenic counterparts. Further experiments are underway to determine whether common pharmacological manipulations can rescue both phenotypes.
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Kalinski, Ashley L., Amar N. Kar, John Craver, Andrew P. Tosolini, James N. Sleigh, Seung Joon Lee, Alicia Hawthorne, et al. "Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition." Journal of Cell Biology 218, no. 6 (May 8, 2019): 1871–90. http://dx.doi.org/10.1083/jcb.201702187.
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Inhibition of histone deacetylase 6 (HDAC6) was shown to support axon growth on the nonpermissive substrates myelin-associated glycoprotein (MAG) and chondroitin sulfate proteoglycans (CSPGs). Though HDAC6 deacetylates α-tubulin, we find that another HDAC6 substrate contributes to this axon growth failure. HDAC6 is known to impact transport of mitochondria, and we show that mitochondria accumulate in distal axons after HDAC6 inhibition. Miro and Milton proteins link mitochondria to motor proteins for axon transport. Exposing neurons to MAG and CSPGs decreases acetylation of Miro1 on Lysine 105 (K105) and decreases axonal mitochondrial transport. HDAC6 inhibition increases acetylated Miro1 in axons, and acetyl-mimetic Miro1 K105Q prevents CSPG-dependent decreases in mitochondrial transport and axon growth. MAG- and CSPG-dependent deacetylation of Miro1 requires RhoA/ROCK activation and downstream intracellular Ca2+ increase, and Miro1 K105Q prevents the decrease in axonal mitochondria seen with activated RhoA and elevated Ca2+. These data point to HDAC6-dependent deacetylation of Miro1 as a mediator of axon growth inhibition through decreased mitochondrial transport.
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Sleigh, James N., Alessio Vagnoni, Alison E. Twelvetrees, and Giampietro Schiavo. "Methodological advances in imaging intravital axonal transport." F1000Research 6 (March 1, 2017): 200. http://dx.doi.org/10.12688/f1000research.10433.1.
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Axonal transport is the active process whereby neurons transport cargoes such as organelles and proteins anterogradely from the cell body to the axon terminal and retrogradely in the opposite direction. Bi-directional transport in axons is absolutely essential for the functioning and survival of neurons and appears to be negatively impacted by both aging and diseases of the nervous system, such as Alzheimer’s disease and amyotrophic lateral sclerosis. The movement of individual cargoes along axons has been studied in vitro in live neurons and tissue explants for a number of years; however, it is currently unclear as to whether these systems faithfully and consistently replicate the in vivo situation. A number of intravital techniques originally developed for studying diverse biological events have recently been adapted to monitor axonal transport in real-time in a range of live organisms and are providing novel insight into this dynamic process. Here, we highlight these methodological advances in intravital imaging of axonal transport, outlining key strengths and limitations while discussing findings, possible improvements, and outstanding questions.
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Takihara, Yuji, Masaru Inatani, Kei Eto, Toshihiro Inoue, Alexander Kreymerman, Seiji Miyake, Shinji Ueno, et al. "In vivo imaging of axonal transport of mitochondria in the diseased and aged mammalian CNS." Proceedings of the National Academy of Sciences 112, no. 33 (August 3, 2015): 10515–20. http://dx.doi.org/10.1073/pnas.1509879112.
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The lack of intravital imaging of axonal transport of mitochondria in the mammalian CNS precludes characterization of the dynamics of axonal transport of mitochondria in the diseased and aged mammalian CNS. Glaucoma, the most common neurodegenerative eye disease, is characterized by axon degeneration and the death of retinal ganglion cells (RGCs) and by an age-related increase in incidence. RGC death is hypothesized to result from disturbances in axonal transport and in mitochondrial function. Here we report minimally invasive intravital multiphoton imaging of anesthetized mouse RGCs through the sclera that provides sequential time-lapse images of mitochondria transported in a single axon with submicrometer resolution. Unlike findings from explants, we show that the axonal transport of mitochondria is highly dynamic in the mammalian CNS in vivo under physiological conditions. Furthermore, in the early stage of glaucoma modeled in adult (4-mo-old) mice, the number of transported mitochondria decreases before RGC death, although transport does not shorten. However, with increasing age up to 23–25 mo, mitochondrial transport (duration, distance, and duty cycle) shortens. In axons, mitochondria-free regions increase and lengths of transported mitochondria decrease with aging, although totally organized transport patterns are preserved in old (23- to 25-mo-old) mice. Moreover, axonal transport of mitochondria is more vulnerable to glaucomatous insults in old mice than in adult mice. These mitochondrial changes with aging may underlie the age-related increase in glaucoma incidence. Our method is useful for characterizing the dynamics of axonal transport of mitochondria and may be applied to other submicrometer structures in the diseased and aged mammalian CNS in vivo.
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Cavalli, Valeria, Pekka Kujala, Judith Klumperman, and Lawrence S. B. Goldstein. "Sunday Driver links axonal transport to damage signaling." Journal of Cell Biology 168, no. 5 (February 28, 2005): 775–87. http://dx.doi.org/10.1083/jcb.200410136.
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Neurons transmit long-range biochemical signals between cell bodies and distant axonal sites or termini. To test the hypothesis that signaling molecules are hitchhikers on axonal vesicles, we focused on the c-Jun NH2-terminal kinase (JNK) scaffolding protein Sunday Driver (syd), which has been proposed to link the molecular motor protein kinesin-1 to axonal vesicles. We found that syd and JNK3 are present on vesicular structures in axons, are transported in both the anterograde and retrograde axonal transport pathways, and interact with kinesin-I and the dynactin complex. Nerve injury induces local activation of JNK, primarily within axons, and activated JNK and syd are then transported primarily retrogradely. In axons, syd and activated JNK colocalize with p150Glued, a subunit of the dynactin complex, and with dynein. Finally, we found that injury induces an enhanced interaction between syd and dynactin. Thus, a mobile axonal JNK–syd complex may generate a transport-dependent axonal damage surveillance system.
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Kar, Amar N., Seung Joon Lee, and Jeffery L. Twiss. "Expanding Axonal Transcriptome Brings New Functions for Axonally Synthesized Proteins in Health and Disease." Neuroscientist 24, no. 2 (June 8, 2017): 111–29. http://dx.doi.org/10.1177/1073858417712668.
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Intra-axonal protein synthesis has been shown to play critical roles in both development and repair of axons. Axons provide long-range connectivity in the nervous system, and disruption of their function and/or structure is seen in several neurological diseases and disorders. Axonally synthesized proteins or losses in axonally synthesized proteins contribute to neurodegenerative diseases, neuropathic pain, viral transport, and survival of axons. Increasing sensitivity of RNA detection and quantitation coupled with methods to isolate axons to purity has shown that a surprisingly complex transcriptome exists in axons. This extends across different species, neuronal populations, and physiological conditions. These studies have helped define the repertoire of neuronal mRNAs that can localize into axons and imply previously unrecognized functions for local translation in neurons. Here, we review the current state of transcriptomics studies of isolated axons, contrast axonal mRNA profiles between different neuronal types and growth states, and discuss how mRNA transport into and translation within axons contribute to neurological disorders.
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Brown, Anthony, Lei Wang, and Peter Jung. "Stochastic Simulation of Neurofilament Transport in Axons: The “Stop-and-Go” Hypothesis." Molecular Biology of the Cell 16, no. 9 (September 2005): 4243–55. http://dx.doi.org/10.1091/mbc.e05-02-0141.
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According to the “stop-and-go” hypothesis of slow axonal transport, cytoskeletal and cytosolic proteins are transported along axons at fast rates but the average velocity is slow because the movements are infrequent and bidirectional. To test whether this hypothesis can explain the kinetics of slow axonal transport in vivo, we have developed a stochastic model of neurofilament transport in axons. We propose that neurofilaments move in both anterograde and retrograde directions along cytoskeletal tracks, alternating between short bouts of rapid movement and short “on-track” pauses, and that they can also temporarily disengage from these tracks, resulting in more prolonged “off-track” pauses. We derive the kinetic parameters of the model from a detailed analysis of the moving and pausing behavior of single neurofilaments in axons of cultured neurons. We show that the model can match the shape, velocity, and spreading of the neurofilament transport waves obtained by radioisotopic pulse labeling in vivo. The model predicts that axonal neurofilaments spend ∼8% of their time on track and ∼97% of their time pausing during their journey along the axon.
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Daniel, Gina R., Patricia J. Sollars, Gary E. Pickard, and Gregory A. Smith. "Pseudorabies Virus Fast Axonal Transport Occurs by a pUS9-Independent Mechanism." Journal of Virology 89, no. 15 (May 20, 2015): 8088–91. http://dx.doi.org/10.1128/jvi.00771-15.
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Reactivation from latency results in transmission of neurotropic herpesviruses from the nervous system to body surfaces, referred to as anterograde axonal trafficking. The virus-encoded protein pUS9 promotes axonal dissemination by sorting virus particles into axons, but whether it is also an effector of fast axonal transport within axons is unknown. To determine the role of pUS9 in anterograde trafficking, we analyzed the axonal transport of pseudorabies virus in the presence and absence of pUS9.
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Okabe, S., and N. Hirokawa. "Axonal transport." Current Opinion in Cell Biology 1, no. 1 (February 1989): 91–97. http://dx.doi.org/10.1016/s0955-0674(89)80043-2.
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Frühbeis, Carsten, Wen Ping Kuo-Elsner, Christina Müller, Kerstin Barth, Leticia Peris, Stefan Tenzer, Wiebke Möbius, et al. "Oligodendrocytes support axonal transport and maintenance via exosome secretion." PLOS Biology 18, no. 12 (December 22, 2020): e3000621. http://dx.doi.org/10.1371/journal.pbio.3000621.
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Neurons extend long axons that require maintenance and are susceptible to degeneration. Long-term integrity of axons depends on intrinsic mechanisms including axonal transport and extrinsic support from adjacent glial cells. The mechanisms of support provided by myelinating oligodendrocytes to underlying axons are only partly understood. Oligodendrocytes release extracellular vesicles (EVs) with properties of exosomes, which upon delivery to neurons improve neuronal viability in vitro. Here, we show that oligodendroglial exosome secretion is impaired in 2 mouse mutants exhibiting secondary axonal degeneration due to oligodendrocyte-specific gene defects. Wild-type oligodendroglial exosomes support neurons by improving the metabolic state and promoting axonal transport in nutrient-deprived neurons. Mutant oligodendrocytes release fewer exosomes, which share a common signature of underrepresented proteins. Notably, mutant exosomes lack the ability to support nutrient-deprived neurons and to promote axonal transport. Together, these findings indicate that glia-to-neuron exosome transfer promotes neuronal long-term maintenance by facilitating axonal transport, providing a novel mechanistic link between myelin diseases and secondary loss of axonal integrity.
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Nakata, Takao, and Nobutaka Hirokawa. "Microtubules provide directional cues for polarized axonal transport through interaction with kinesin motor head." Journal of Cell Biology 162, no. 6 (September 15, 2003): 1045–55. http://dx.doi.org/10.1083/jcb.200302175.
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Post-Golgi carriers of various newly synthesized axonal membrane proteins, which possess kinesin (KIF5)-driven highly processive motility, were transported from the TGN directly to axons. We found that KIF5 has a preference to the microtubules in the initial segment of axon. Low dose paclitaxel treatment caused missorting of KIF5, as well as axonal membrane proteins to the tips of dendrites. Microtubules in the initial segment of axons showed a remarkably high affinity to EB1–YFP, which was known to bind the tips of growing microtubules. These findings revealed unique features of the microtubule cytoskeletons in the initial segment, and suggested that they provide directional information for polarized axonal transport.
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Guedes-Dias, Pedro, and Erika L. F. Holzbaur. "Axonal transport: Driving synaptic function." Science 366, no. 6462 (October 10, 2019): eaaw9997. http://dx.doi.org/10.1126/science.aaw9997.
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The intracellular transport system in neurons is specialized to an extraordinary degree, enabling the delivery of critical cargo to sites in axons or dendrites that are far removed from the cell center. Vesicles formed in the cell body are actively transported by kinesin motors along axonal microtubules to presynaptic sites that can be located more than a meter away. Both growth factors and degradative vesicles carrying aged organelles or aggregated proteins take the opposite route, driven by dynein motors. Distance is not the only challenge; precise delivery of cargos to sites of need must also be accomplished. For example, localized delivery of presynaptic components to hundreds of thousands of “en passant” synapses distributed along the length of a single axon in some neuronal subtypes provides a layer of complexity that must be successfully navigated to maintain synaptic transmission. We review recent advances in the field of axonal transport, with a focus on conceptual developments, and highlight our growing quantitative understanding of neuronal trafficking and its role in maintaining the synaptic function that underlies higher cognitive processes such as learning and memory.
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Brown, Anthony. "Axonal transport of membranous and nonmembranous cargoes." Journal of Cell Biology 160, no. 6 (March 17, 2003): 817–21. http://dx.doi.org/10.1083/jcb.200212017.
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Membranous and nonmembranous cargoes are transported along axons in the fast and slow components of axonal transport, respectively. Recent observations on the movement of cytoskeletal polymers in axons suggest that slow axonal transport is generated by fast motors and that the slow rate is due to rapid movements interrupted by prolonged pauses. This supports a unified perspective for fast and slow axonal transport based on rapid movements of diverse cargo structures that differ in the proportion of the time that they spend moving. A Flash feature accompanies this Mini-Review.
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Dias, Mariana Santana, Xiaoyue Luo, Vinicius Toledo Ribas, Hilda Petrs-Silva, and Jan Christoph Koch. "The Role of Axonal Transport in Glaucoma." International Journal of Molecular Sciences 23, no. 7 (April 1, 2022): 3935. http://dx.doi.org/10.3390/ijms23073935.
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Glaucoma is a neurodegenerative disease that affects the retinal ganglion cells (RGCs) and leads to progressive vision loss. The first pathological signs can be seen at the optic nerve head (ONH), the structure where RGC axons leave the retina to compose the optic nerve. Besides damage of the axonal cytoskeleton, axonal transport deficits at the ONH have been described as an important feature of glaucoma. Axonal transport is essential for proper neuronal function, including transport of organelles, synaptic components, vesicles, and neurotrophic factors. Impairment of axonal transport has been related to several neurodegenerative conditions. Studies on axonal transport in glaucoma include analysis in different animal models and in humans, and indicate that its failure happens mainly in the ONH and early in disease progression, preceding axonal and somal degeneration. Thus, a better understanding of the role of axonal transport in glaucoma is not only pivotal to decipher disease mechanisms but could also enable early therapies that might prevent irreversible neuronal damage at an early time point. In this review we present the current evidence of axonal transport impairment in glaucomatous neurodegeneration and summarize the methods employed to evaluate transport in this disease.
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Campenot, B., K. Lund, and D. L. Senger. "Delivery of newly synthesized tubulin to rapidly growing distal axons of sympathetic neurons in compartmented cultures." Journal of Cell Biology 135, no. 3 (November 1, 1996): 701–9. http://dx.doi.org/10.1083/jcb.135.3.701.
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Growing axons receive a substantial supply of tubulin and other proteins delivered from sites of synthesis in the cell body by slow axonal transport. To investigate the mechanism of tubulin transport most previous studies have used in vitro models in which the transport of microtubules can be visualized during brief periods of growth. To investigate total tubulin transport in neurons displaying substantial growth over longer periods, we used rat sympathetic neurons in compartmented cultures. Tubulin synthesized during pulses of [35S]methionine was separated from other proteins by immunoprecipitation with monoclonal antibodies to alpha and beta tubulin, further separated on SDS-PAGE, and quantified by phosphorimaging. Results showed that 90% of newly synthesized tubulin moved into the distal axons within 2 d. Furthermore, the leading edge of tubulin was transported at a velocity faster than 4 mm/d, more than four times the rate of axon elongation. This velocity did not diminish with distance from the cell body, suggesting that the transport system is capable of distributing newly synthesized tubulin to growth cones throughout the axonal tree. Neither diffusion nor the an mass transport of axonal microtubules can account for the velocity and magnitude of tubulin transport that was observed. Thus, it is likely that most of the newly synthesized tubulin was supplied to the growing axonal tree in subunit form such as a heterodimer or an oligomer considerably smaller than a microtubule.
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Miranda-Saksena, Monica, Ross A. Boadle, Russell J. Diefenbach, and Anthony L. Cunningham. "Dual Role of Herpes Simplex Virus 1 pUS9 in Virus Anterograde Axonal Transport and Final Assembly in Growth Cones in Distal Axons." Journal of Virology 90, no. 5 (December 23, 2015): 2653–63. http://dx.doi.org/10.1128/jvi.03023-15.
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ABSTRACTThe herpes simplex virus type 1 (HSV-1) envelope protein pUS9 plays an important role in virus anterograde axonal transport and spread from neuronal axons. In this study, we used both confocal microscopy and transmission electron microscopy (TEM) to examine the role of pUS9 in the anterograde transport and assembly of HSV-1 in the distal axon of human and rat dorsal root ganglion (DRG) neurons using US9 deletion (US9−), repair (US9R), and wild-type (strain F, 17, and KOS) viruses. Using confocal microscopy and single and trichamber culture systems, we observed a reduction but not complete block in the anterograde axonal transport of capsids to distal axons as well as a marked (∼90%) reduction in virus spread from axons to Vero cells with the US9 deletion viruses. Axonal transport of glycoproteins (gC, gD, and gE) was unaffected. Using TEM, there was a marked reduction or absence of enveloped capsids, in varicosities and growth cones, in KOS strain and US9 deletion viruses, respectively. Capsids (40 to 75%) in varicosities and growth cones infected with strain 17, F, and US9 repair viruses were fully enveloped compared to less than 5% of capsids found in distal axons infected with the KOS strain virus (which also lacks pUS9) and still lower (<2%) with the US9 deletion viruses. Hence, there was a secondary defect in virus assembly in distal axons in the absence of pUS9 despite the presence of key envelope proteins. Overall, our study supports a dual role for pUS9, first in anterograde axonal transport and second in virus assembly in growth cones in distal axons.IMPORTANCEHSV-1 has evolved mechanisms for its efficient transport along sensory axons and subsequent spread from axons to epithelial cells after reactivation. In this study, we show that deletion of the envelope protein pUS9 leads to defects in virus transport along axons (partial defect) and in virus assembly and egress from growth cones (marked defect). Virus assembly and exit in the neuronal cell body are not impaired in the absence of pUS9. Thus, our findings indicate that pUS9 contributes to the overall HSV-1 anterograde axonal transport, including a major role in virus assembly at the axon terminus, which is not essential in the neuronal cell body. Overall, our data suggest that the process of virus assembly at the growth cones differs from that in the neuronal cell body and that HSV-1 has evolved different mechanisms for virus assembly and exit from different cellular compartments.
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Hoffman, P. N., G. W. Thompson, J. W. Griffin, and D. L. Price. "Changes in neurofilament transport coincide temporally with alterations in the caliber of axons in regenerating motor fibers." Journal of Cell Biology 101, no. 4 (October 1, 1985): 1332–40. http://dx.doi.org/10.1083/jcb.101.4.1332.
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The delivery of neurofilaments via axonal transport has been proposed as an important mechanism for regulating axonal caliber. If this hypothesis is correct, alterations in axonal caliber should appear coincident with changes in the delivery of neurofilaments to the axon. The purpose of this study was to determine whether alterations in the caliber of axons in the proximal stumps of transected motor fibers precede, coincide with, or occur substantially later than changes in the delivery of neurofilaments via axonal transport. Between 3 d and 12 wk after crushing the sciatic nerves of 7-wk-old rats, lumbar motor neurons were labeled by the intraspinal injection of [35S]methionine. In neurons labeled between 3 d and 6 wk after axotomy, the relative amount of neurofilament protein in the slow component, as reflected by the ratio of the radioactivities of the 145-kD neurofilament protein to tubulin, was reduced to 30-40% of the control value. Moreover, as determined by immunoreactivity on blots, the amounts of neurofilament protein and tubulin in these nerve fibers were reduced fourfold and twofold, respectively. Thus, changes in the ratio of labeled neurofilament protein to tubulin correlated with comparable changes in the quantities of these proteins in nerve fibers. This decrease in the quantity of neurofilament proteins delivered to axons coincided temporally with reductions in axonal caliber. After regeneration occurred, the delivery of neurofilament proteins returned to pre-axotomy levels (i.e., 8 wk after axotomy), and caliber was restored with resumption of normal age-related radial growth of these axons. Thus, changes in axonal caliber coincided temporally with alterations in the delivery of neurofilament proteins. These results suggest that the majority of neurofilaments in these motor fibers continuously move in the anterograde direction as part of the slow component of axonal transport and that the transport of neurofilaments plays an important role in regulating the caliber of these axons.
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Carmichael, Stephen W., and W. Stephen Brimijoin. "Looking at Slow Axonal Transport." Microscopy Today 4, no. 9 (November 1996): 3–5. http://dx.doi.org/10.1017/s1551929500065299.
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Neurons are about as polarized as cells ever get. Their axonal process can extend a distance that is up to a million times the diameter of the nerve cell body. Axons have none of the ribosomal machinery responsible for protein synthesis, so all neuronal proteins and peptides must be manufactured near the nucleus and carried out to the periphery. This distribution involves at least two distinct mechanisms, fast axonal transport, moving at almost 500 mm per day, and slow axonal transport, moving only 0.1 to 3 mm per day. It turns out that proteins of the neuronal cytoskeleton, along with many soluble cytosolic proteins, are transported exclusively by the slower process.
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Krieg, Justin L., Anna V. Leonard, Renée J. Turner, and Frances Corrigan. "Identifying the Phenotypes of Diffuse Axonal Injury Following Traumatic Brain Injury." Brain Sciences 13, no. 11 (November 20, 2023): 1607. http://dx.doi.org/10.3390/brainsci13111607.
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Diffuse axonal injury (DAI) is a significant feature of traumatic brain injury (TBI) across all injury severities and is driven by the primary mechanical insult and secondary biochemical injury phases. Axons comprise an outer cell membrane, the axolemma which is anchored to the cytoskeletal network with spectrin tetramers and actin rings. Neurofilaments act as space-filling structural polymers that surround the central core of microtubules, which facilitate axonal transport. TBI has differential effects on these cytoskeletal components, with axons in the same white matter tract showing a range of different cytoskeletal and axolemma alterations with different patterns of temporal evolution. These require different antibodies for detection in post-mortem tissue. Here, a comprehensive discussion of the evolution of axonal injury within different cytoskeletal elements is provided, alongside the most appropriate methods of detection and their temporal profiles. Accumulation of amyloid precursor protein (APP) as a result of disruption of axonal transport due to microtubule failure remains the most sensitive marker of axonal injury, both acutely and chronically. However, a subset of injured axons demonstrate different pathology, which cannot be detected via APP immunoreactivity, including degradation of spectrin and alterations in neurofilaments. Furthermore, recent work has highlighted the node of Ranvier and the axon initial segment as particularly vulnerable sites to axonal injury, with loss of sodium channels persisting beyond the acute phase post-injury in axons without APP pathology. Given the heterogenous response of axons to TBI, further characterization is required in the chronic phase to understand how axonal injury evolves temporally, which may help inform pharmacological interventions.
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Lorenzo, Damaris N., Alexandra Badea, Ruobo Zhou, Peter J. Mohler, Xiaowei Zhuang, and Vann Bennett. "βII-spectrin promotes mouse brain connectivity through stabilizing axonal plasma membranes and enabling axonal organelle transport." Proceedings of the National Academy of Sciences 116, no. 31 (June 17, 2019): 15686–95. http://dx.doi.org/10.1073/pnas.1820649116.
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βII-spectrin is the generally expressed member of the β-spectrin family of elongated polypeptides that form micrometer-scale networks associated with plasma membranes. We addressed in vivo functions of βII-spectrin in neurons by knockout of βII-spectrin in mouse neural progenitors. βII-spectrin deficiency caused severe defects in long-range axonal connectivity and axonal degeneration. βII-spectrin–null neurons exhibited reduced axon growth, loss of actin–spectrin-based periodic membrane skeleton, and impaired bidirectional axonal transport of synaptic cargo. We found that βII-spectrin associates with KIF3A, KIF5B, KIF1A, and dynactin, implicating spectrin in the coupling of motors and synaptic cargo. βII-spectrin required phosphoinositide lipid binding to promote axonal transport and restore axon growth. Knockout of ankyrin-B (AnkB), a βII-spectrin partner, primarily impaired retrograde organelle transport, while double knockout of βII-spectrin and AnkB nearly eliminated transport. Thus, βII-spectrin promotes both axon growth and axon stability through establishing the actin–spectrin-based membrane-associated periodic skeleton as well as enabling axonal transport of synaptic cargo.
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Nakata, Takao, Shinsuke Niwa, Yasushi Okada, Franck Perez, and Nobutaka Hirokawa. "Preferential binding of a kinesin-1 motor to GTP-tubulin–rich microtubules underlies polarized vesicle transport." Journal of Cell Biology 194, no. 2 (July 18, 2011): 245–55. http://dx.doi.org/10.1083/jcb.201104034.
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Polarized transport in neurons is fundamental for the formation of neuronal circuitry. A motor domain–containing truncated KIF5 (a kinesin-1) recognizes axonal microtubules, which are enriched in EB1 binding sites, and selectively accumulates at the tips of axons. However, it remains unknown what cue KIF5 recognizes to result in this selective accumulation. We found that axonal microtubules were preferentially stained by the anti–GTP-tubulin antibody hMB11. Super-resolution microscopy combined with EM immunocytochemistry revealed that hMB11 was localized at KIF5 attachment sites. In addition, EB1, which binds preferentially to guanylyl-methylene-diphosphate (GMPCPP) microtubules in vitro, recognized hMB11 binding sites on axonal microtubules. Further, expression of hMB11 antibody in neurons disrupted the selective accumulation of truncated KIF5 in the axon tips. In vitro studies revealed approximately threefold stronger binding of KIF5 motor head to GMPCPP microtubules than to GDP microtubules. Collectively, these data suggest that the abundance of GTP-tubulin in axonal microtubules may underlie selective KIF5 localization and polarized axonal vesicular transport.
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Hurd, Daryl D., and William M. Saxton. "Kinesin Mutations Cause Motor Neuron Disease Phenotypes by Disrupting Fast Axonal Transport in Drosophila." Genetics 144, no. 3 (November 1, 1996): 1075–85. http://dx.doi.org/10.1093/genetics/144.3.1075.
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Abstract Previous work has shown that mutation of the gene that encodes the microtubule motor subunit kinesin heavy chain (Khc) in Drosophila inhibits neuronal sodium channel activity, action potentials and neurotransmitter secretion. These physiological defects cause progressive distal paralysis in larvae. To identify the cellular defects that cause these phenotypes, larval nerves were studied by light and electron microscopy. The axons of Khc mutants develop dramatic focal swellings along their lengths. The swellings are packed with fast axonal transport cargoes including vesicles, synaptic membrane proteins, mitochondria and prelysosomal organelles, but not with slow axonal transport cargoes such as cytoskeletal elements. Khc mutations also impair the development of larval motor axon terminals, causing dystrophic morphology and marked reductions in synaptic bouton numbers. These observations suggest that as the concentration of maternally provided wild-type KHC decreases, axonal organelles transported by kinesin periodically stall. This causes organelle jams that disrupt retrograde as well as anterograde fast axonal transport, leading to defective action potentials, dystrophic terminals, reduced transmitter secretion and progressive distal paralysis. These phenotypes parallel the pathologies of some vertebrate motor neuron diseases, including some forms of amyotrophic lateral sclerosis (ALS), and suggest that impaired fast axonal transport is a key element in those diseases.
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Duncan, Jason E., and Lawrence S. B. Goldstein. "The Genetics of Axonal Transport and Axonal Transport Disorders." PLoS Genetics 2, no. 9 (September 29, 2006): e124. http://dx.doi.org/10.1371/journal.pgen.0020124.
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Satkeviciute, Ieva, George Goodwin, Geoffrey M. Bove, and Andrew Dilley. "Time course of ongoing activity during neuritis and following axonal transport disruption." Journal of Neurophysiology 119, no. 5 (May 1, 2018): 1993–2000. http://dx.doi.org/10.1152/jn.00882.2017.
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Local nerve inflammation (neuritis) leads to ongoing activity and axonal mechanical sensitivity (AMS) along intact nociceptor axons and disrupts axonal transport. This phenomenon forms the most feasible cause of radiating pain, such as sciatica. We have previously shown that axonal transport disruption without inflammation or degeneration also leads to AMS but does not cause ongoing activity at the time point when AMS occurs, despite causing cutaneous hypersensitivity. However, there have been no systematic studies of ongoing activity during neuritis or noninflammatory axonal transport disruption. In this study, we present the time course of ongoing activity from primary sensory neurons following neuritis and vinblastine-induced axonal transport disruption. Whereas 24% of C/slow Aδ-fiber neurons had ongoing activity during neuritis, few (<10%) A- and C-fiber neurons showed ongoing activity 1–15 days following vinblastine treatment. In contrast, AMS increased transiently at the vinblastine treatment site, peaking on days 4–5 (28% of C/slow Aδ-fiber neurons) and resolved by day 15. Conduction velocities were slowed in all groups. In summary, the disruption of axonal transport without inflammation does not lead to ongoing activity in sensory neurons, including nociceptors, but does cause a rapid and transient development of AMS. Because it is proposed that AMS underlies mechanically induced radiating pain, and a transient disruption of axonal transport (as previously reported) leads to transient AMS, it follows that processes that disrupt axonal transport, such as neuritis, must persist to maintain AMS and the associated symptoms. NEW & NOTEWORTHY Many patients with radiating pain lack signs of nerve injury on clinical examination but may have neuritis, which disrupts axonal transport. We have shown that axonal transport disruption does not induce ongoing activity in primary sensory neurons but does cause transient axonal mechanical sensitivity. The present data complete a profile of key axonal sensitivities following axonal transport disruption. Collectively, this profile supports that an active peripheral process is necessary for maintained axonal sensitivities.
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Kratchmarov, R., L. W. Enquist, and M. P. Taylor. "Us9-Independent Axonal Sorting and Transport of the Pseudorabies Virus Glycoprotein gM." Journal of Virology 89, no. 12 (April 1, 2015): 6511–14. http://dx.doi.org/10.1128/jvi.00625-15.
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Axonal sorting and transport of fully assembled pseudorabies virus (PRV) virions is dependent on the viral protein Us9. Here we identify a Us9-independent mechanism for axonal localization of viral glycoprotein M (gM). We detected gM-mCherry assemblies transporting in the anterograde direction in axons. Furthermore, unlabeled gM, but not glycoprotein B, was detected by Western blotting in isolated axons during Us9-null PRV infection. These results suggest that gM differs from other viral proteins regarding axonal transport properties.
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Xia, Chun-Hong, Elizabeth A. Roberts, Lu-Shiun Her, Xinran Liu, David S. Williams, Don W. Cleveland, and Lawrence S. B. Goldstein. "Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A." Journal of Cell Biology 161, no. 1 (April 7, 2003): 55–66. http://dx.doi.org/10.1083/jcb.200301026.
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To test the hypothesis that fast anterograde molecular motor proteins power the slow axonal transport of neurofilaments (NFs), we used homologous recombination to generate mice lacking the neuronal-specific conventional kinesin heavy chain, KIF5A. Because null KIF5A mutants die immediately after birth, a synapsin-promoted Cre-recombinase transgene was used to direct inactivation of KIF5A in neurons postnatally. Three fourths of such mutant mice exhibited seizures and death at around 3 wk of age; the remaining animals survived to 3 mo or longer. In young mutant animals, fast axonal transport appeared to be intact, but NF-H, as well as NF-M and NF-L, accumulated in the cell bodies of peripheral sensory neurons accompanied by a reduction in sensory axon caliber. Older animals also developed age-dependent sensory neuron degeneration, an accumulation of NF subunits in cell bodies and a reduction in axons, loss of large caliber axons, and hind limb paralysis. These data support the hypothesis that a conventional kinesin plays a role in the microtubule-dependent slow axonal transport of at least one cargo, the NF proteins.
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Zheng, Yanrong, Xiangnan Zhang, Xiaoli Wu, Lei Jiang, Anil Ahsan, Shijia Ma, Ziyu Xiao, et al. "Somatic autophagy of axonal mitochondria in ischemic neurons." Journal of Cell Biology 218, no. 6 (April 12, 2019): 1891–907. http://dx.doi.org/10.1083/jcb.201804101.
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Mitophagy protects against ischemic neuronal injury by eliminating damaged mitochondria, but it is unclear how mitochondria in distal axons are cleared. We find that oxygen and glucose deprivation-reperfusion reduces mitochondrial content in both cell bodies and axons. Axonal mitochondria elimination was not abolished in Atg7fl/fl;nes-Cre neurons, suggesting the absence of direct mitophagy in axons. Instead, axonal mitochondria were enwrapped by autophagosomes in soma and axon-derived mitochondria prioritized for elimination by autophagy. Intriguingly, axonal mitochondria showed prompt loss of anterograde motility but increased retrograde movement upon reperfusion. Anchoring of axonal mitochondria by syntaphilin blocked neuronal mitophagy and aggravated injury. Conversely, induced binding of mitochondria to dynein reinforced retrograde transport and enhanced mitophagy to prevent mitochondrial dysfunction and attenuate neuronal injury. Therefore, we reveal somatic autophagy of axonal mitochondria in ischemic neurons and establish a direct link of retrograde mitochondrial movement with mitophagy. Our findings may provide a new concept for reducing ischemic neuronal injury by correcting mitochondrial motility.
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Baas, P. W., and F. J. Ahmad. "The transport properties of axonal microtubules establish their polarity orientation." Journal of Cell Biology 120, no. 6 (March 15, 1993): 1427–37. http://dx.doi.org/10.1083/jcb.120.6.1427.
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It is well established that axonal microtubules (MTs) are uniformly oriented with their plus ends distal to the neuronal cell body (Heidemann, S. R., J. M. Landers, and M. A. Hamborg. 1981. J. Cell Biol. 91:661-665). However, the mechanisms by which these MTs achieve their uniform polarity orientation are unknown. Current models for axon growth differ with regard to the contributions of MT assembly and transport to the organization and elaboration of the axonal MT array. Do the transport properties or assembly properties of axonal MTs determine their polarity orientation? To distinguish between these possibilities, we wished to study the initiation and outgrowth of axons under conditions that would arrest MT assembly while maintaining substantial levels of preexisting polymer in the cell body that could still be transported into the axon. We found that we could accomplish this by culturing rat sympathetic neurons in the presence of nanomolar levels of vinblastine. In concentrations of the drug up to and including 100 nM, the neurons actively extend axons. The vinblastine-axons are shorter than control axons, but clearly contain MTs. To quantify the effects of the drug on MT mass, we compared the levels of polymer throughout the cell bodies and axons of neurons cultured overnight in the presence of 0, 16, and 50 nM vinblastine with the levels of MT polymer in freshly plated neurons before axon outgrowth. Without drug, the total levels of polymer increase by roughly twofold. At 16 nM vinblastine, the levels of polymer are roughly equal to the levels in freshly plated neurons, while at 50 nM, the levels of polymer are reduced by about half this amount. Thus, 16 nM vinblastine acts as a "kinetic stabilizer" of MTs, while 50 nM results in some net MT disassembly. At both drug concentrations, there is a progressive increase in the levels of MT polymer in the axons as they grow, and a corresponding depletion of polymer from the cell body. These results indicate that highly efficient mechanisms exist in the neuron to transport preassembled MTs from the cell body into the axon. These mechanisms are active even at the expense of the cell body, and even under conditions that promote some MT disassembly in the neuron. MT polarity analyses indicate that the MTs within the vinblastine-axons, like those in control axons, are uniformly plus-end-distal.(ABSTRACT TRUNCATED AT 400 WORDS)
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Miller, K. E., and H. C. Joshi. "Tubulin transport in neurons." Journal of Cell Biology 133, no. 6 (June 15, 1996): 1355–66. http://dx.doi.org/10.1083/jcb.133.6.1355.
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A question of broad importance in cellular neurobiology has been, how is microtubule cytoskeleton of the axon organized? It is of particular interest because of the history of conflicting results concerning the form in which tubulin is transported in the axon. While many studies indicate a stationary nature of axonal microtubules, a recent series of experiments reports that microtubules are recruited into axons of neurons grown in the presence of a microtubule-inhibitor, vinblastine (Baas, P.W., and F.J. Ahmad. 1993.J. Cell Biol. 120:1427-1437: Ahmad F.J., and P.W. Baas. 1995. J. Cell Sci, 108:2761-2769; Sharp, D.J., W. Yu, and P.W. Baas. 1995. J. Cell Biol, 130:93-103; Yu, W., and P.W. Baas. 1995. J. Neurosci. 15:6827-6833.). Since vinblastine stabilizes bulk microtubule-dynamics in vitro, it was concluded that preformed microtubules moved into newly grown axons. By visualizing the polymerization of injected fluorescent tubulin, we show that substantial microtubule polymerization occurs in neurons grown at reported vinblastine concentrations. Vinblastine inhibits, in a concentration-dependent manner, both neurite outgrowth and microtubule assembly. More importantly, the neuron growth conditions of low vinblastine concentration allowed us to visualize the footprints of the tubulin wave as it polymerized and depolymerized during its slow axonal transport. In contrast, depolymerization resistant fluorescent microtubules did not move when injected in neurons. We show that tubulin subunits, not microtubules, are the primary form of tubulin transport in neurons.
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Heriot, K., P. Gambetti, and R. J. Lasek. "Proteins transported in slow components a and b of axonal transport are distributed differently in the transverse plane of the axon." Journal of Cell Biology 100, no. 4 (April 1, 1985): 1167–72. http://dx.doi.org/10.1083/jcb.100.4.1167.
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The distribution of the proteins migrating with the slow components a (SCa) and b (SCb) of axonal transport were studied in cross-sections of axons with electron microscope autoradiography. Radiolabeled amino acids were injected into the hypoglossal nucleus of rabbits and after 15 d, the animals were killed. Hypoglossal nerves were processed either for SDS-polyacrylamide gel electrophoresis fluorography to identify and locate the two components of slow transport, or for quantitative electron microscope autoradiography. Proteins transported in SCa were found to be uniformly distributed within the cross-section of the axon. Labeled SCb proteins were also found throughout the axonal cross-section, but the subaxolemmal region of the axon contained 2.5 times more SCb radioactivity than any comparable area in the remainder of the axon.
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Saksena, Monica Miranda, Hiroyuki Wakisaka, Bibing Tijono, Ross A. Boadle, Frazer Rixon, Hirotaka Takahashi, and Anthony L. Cunningham. "Herpes Simplex Virus Type 1 Accumulation, Envelopment, and Exit in Growth Cones and Varicosities in Mid-Distal Regions of Axons." Journal of Virology 80, no. 7 (April 1, 2006): 3592–606. http://dx.doi.org/10.1128/jvi.80.7.3592-3606.2006.
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ABSTRACT The mechanism of anterograde transport of alphaherpesviruses in axons remains controversial. This study examined the transport, assembly, and egress of herpes simplex virus type 1 (HSV-1) in mid- and distal axons of infected explanted human fetal dorsal root ganglia using confocal microscopy and transmission electron microscopy (TEM) at 19, 24, and 48 h postinfection (p.i.). Confocal-microscopy studies showed that although capsid (VP5) and tegument (UL37) proteins were not uniformly present in axons until 24 h p.i., they colocalized with envelope (gG) proteins in axonal varicosities and in growth cones at 24 and 48 h p.i. TEM of longitudinal sections of axons in situ showed enveloped and unenveloped capsids in the axonal varicosities and growth cones, whereas in the midregion of the axons, predominantly unenveloped capsids were observed. Partially enveloped capsids, apparently budding into vesicles, were observed in axonal varicosities and growth cones, but not during viral attachment and entry into axons. Tegument proteins (VP22) were found associated with vesicles in growth cones, either alone or together with envelope (gD) proteins, by transmission immunoelectron microscopy. Extracellular virions were observed adjacent to axonal varicosities and growth cones, with some virions observed in crescent-shaped invaginations of the axonal plasma membrane, suggesting exit at these sites. These findings suggest that varicosities and growth cones are probable sites of HSV-1 envelopment of at least a proportion of virions in the mid- to distal axon. Envelopment probably occurs by budding of capsids into vesicles with associated tegument and envelope proteins. Virions appear to exit from these sites by exocytosis.
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Setou, Mitsutoshi, Takahiro Hayasaka, and Ikuko Yao. "Axonal transport versus dendritic transport." Journal of Neurobiology 58, no. 2 (2003): 201–6. http://dx.doi.org/10.1002/neu.10324.
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Nixon, Ralph A. "Slow axonal transport." Current Biology 2, no. 3 (March 1992): 155. http://dx.doi.org/10.1016/0960-9822(92)90270-k.
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Nixon, Ralph A. "Slow axonal transport." Current Opinion in Cell Biology 4, no. 1 (February 1992): 8–14. http://dx.doi.org/10.1016/0955-0674(92)90052-e.
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Twelvetrees, Alison, Adam G. Hendricks, and Erika L. F. Holzbaur. "SnapShot: Axonal Transport." Cell 149, no. 4 (May 2012): 950–950. http://dx.doi.org/10.1016/j.cell.2012.05.001.
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Jiménez-Mateos, Eva-María, Christian González-Billault, Hana N. Dawson, Michael P. Vitek, and Jesús Avila. "Role of MAP1B in axonal retrograde transport of mitochondria." Biochemical Journal 397, no. 1 (June 14, 2006): 53–59. http://dx.doi.org/10.1042/bj20060205.
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The MAPs (microtubule-associated proteins) MAP1B and tau are well known for binding to microtubules and stabilizing these structures. An additional role for MAPs has emerged recently where they appear to participate in the regulation of transport of cargos on the microtubules found in axons. In this role, tau has been associated with the regulation of anterograde axonal transport. We now report that MAP1B is associated with the regulation of retrograde axonal transport of mitochondria. This finding potentially provides precise control of axonal transport by MAPs at several levels: controlling the anterograde or retrograde direction of transport depending on the type of MAP involved, controlling the speed of transport and controlling the stability of the microtubule tracks upon which transport occurs.
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Volpicelli-Daley, Laura A., Karen L. Gamble, Christine E. Schultheiss, Dawn M. Riddle, Andrew B. West, and Virginia M. Y. Lee. "Formation of α-synuclein Lewy neurite–like aggregates in axons impedes the transport of distinct endosomes." Molecular Biology of the Cell 25, no. 25 (December 15, 2014): 4010–23. http://dx.doi.org/10.1091/mbc.e14-02-0741.
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Aggregates of α-synuclein (α-syn) accumulate in neurons in Parkinson's disease and other synucleinopathies. These inclusions predominantly localize to axons even in the early stages of the disease, but their affect on axon function has remained unknown. Previously we established a model in which the addition of preformed α-syn fibrils to primary neurons seeds formation of insoluble α-syn inclusions built from endogenously expressed α-syn that closely recapitulate the neuropathological phenotypes of Lewy neurites found in human diseased brains. Here we show, using live-cell imaging, that immobile α-syn inclusions accumulate in axons from the recruitment of α-syn located on mobile α-syn–positive vesicles. Ultrastructural analyses and live imaging demonstrate that α-syn accumulations do not cause a generalized defect in axonal transport; the inclusions do not fill the axonal cytoplasm, disrupt the microtubule cytoskeleton, or affect the transport of synaptophysin or mitochondria. However, the α-syn aggregates impair the transport of Rab7 and TrkB receptor–containing endosomes, as well as autophagosomes. In addition, the TrkB receptor–associated signaling molecule pERK5 accumulates in α-syn aggregate–bearing neurons. Thus α-syn pathology impairs axonal transport of signaling and degradative organelles. These early effects of α-syn accumulations may predict points of intervention in the neurodegenerative process.
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Gowrishankar, Swetha, Yumei Wu, and Shawn M. Ferguson. "Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology." Journal of Cell Biology 216, no. 10 (August 7, 2017): 3291–305. http://dx.doi.org/10.1083/jcb.201612148.
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Lysosomes robustly accumulate within axonal swellings at Alzheimer’s disease (AD) amyloid plaques. However, the underlying mechanisms and disease relevance of such lysosome accumulations are not well understood. Motivated by these problems, we identified JNK-interacting protein 3 (JIP3) as an important regulator of axonal lysosome transport and maturation. JIP3 knockout mouse neuron primary cultures accumulate lysosomes within focal axonal swellings that resemble the dystrophic axons at amyloid plaques. These swellings contain high levels of amyloid precursor protein processing enzymes (BACE1 and presenilin 2) and are accompanied by elevated Aβ peptide levels. The in vivo importance of the JIP3-dependent regulation of axonal lysosomes was revealed by the worsening of the amyloid plaque pathology arising from JIP3 haploinsufficiency in a mouse model of AD. These results establish the critical role of JIP3-dependent axonal lysosome transport in regulating amyloidogenic amyloid precursor protein processing and support a model wherein Aβ production is amplified by plaque-induced axonal lysosome transport defects.
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Martinat, Cécile, Nadine Jarousse, Marie-Christine Prévost, and Michel Brahic. "The GDVII Strain of Theiler’s Virus Spreads via Axonal Transport." Journal of Virology 73, no. 7 (July 1, 1999): 6093–98. http://dx.doi.org/10.1128/jvi.73.7.6093-6098.1999.
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ABSTRACT Following intracerebral inoculation, the DA strain of Theiler’s virus sequentially infects neurons in the gray matter and glial cells in the white matter of the spinal cord. It persists in the latter throughout the life of the animal. Several observations suggest that the virus spreads from the gray to the white matter by axonal transport. In contrast, the neurovirulent GDVII strain causes a fatal encephalitis with lytic infection of neurons. It does not infect the white matter of the spinal cord efficiently and does not persist in survivors. The inability of this virus to infect the white matter could be due to a defect in axonal transport. Using footpad inoculations, we showed that the GDVII strain is, in fact, transported in axons. Transport was prevented by sectioning the sciatic nerve. The kinetics of transport and experiments using colchicine suggested that the virus uses microtubule-associated fast axonal transport. Our results show that a cardiovirus can spread by fast axonal transport and suggest that the inability of the GDVII strain to infect the white matter is not due to a defect in axonal transport.
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González, Carolina, José Cánovas, Javiera Fresno, Eduardo Couve, Felipe A. Court, and Andrés Couve. "Axons provide the secretory machinery for trafficking of voltage-gated sodium channels in peripheral nerve." Proceedings of the National Academy of Sciences 113, no. 7 (February 2, 2016): 1823–28. http://dx.doi.org/10.1073/pnas.1514943113.
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The regulation of the axonal proteome is key to generate and maintain neural function. Fast and slow axoplasmic waves have been known for decades, but alternative mechanisms to control the abundance of axonal proteins based on local synthesis have also been identified. The presence of the endoplasmic reticulum has been documented in peripheral axons, but it is still unknown whether this localized organelle participates in the delivery of axonal membrane proteins. Voltage-gated sodium channels are responsible for action potentials and are mostly concentrated in the axon initial segment and nodes of Ranvier. Despite their fundamental role, little is known about the intracellular trafficking mechanisms that govern their availability in mature axons. Here we describe the secretory machinery in axons and its contribution to plasma membrane delivery of sodium channels. The distribution of axonal secretory components was evaluated in axons of the sciatic nerve and in spinal nerve axons after in vivo electroporation. Intracellular protein trafficking was pharmacologically blocked in vivo and in vitro. Axonal voltage-gated sodium channel mRNA and local trafficking were examined by RT-PCR and a retention-release methodology. We demonstrate that mature axons contain components of the endoplasmic reticulum and other biosynthetic organelles. Axonal organelles and sodium channel localization are sensitive to local blockade of the endoplasmic reticulum to Golgi transport. More importantly, secretory organelles are capable of delivering sodium channels to the plasma membrane in isolated axons, demonstrating an intrinsic capacity of the axonal biosynthetic route in regulating the axonal proteome in mammalian axons.
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Chen, Ying-Chun, Hao-Ru Huang, Chia-Hao Hsu, and Chan-Yen Ou. "CRMP/UNC-33 organizes microtubule bundles for KIF5-mediated mitochondrial distribution to axon." PLOS Genetics 17, no. 2 (February 11, 2021): e1009360. http://dx.doi.org/10.1371/journal.pgen.1009360.
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Neurons are highly specialized cells with polarized cellular processes and subcellular domains. As vital organelles for neuronal functions, mitochondria are distributed by microtubule-based transport systems. Although the essential components of mitochondrial transport including motors and cargo adaptors are identified, it is less clear how mitochondrial distribution among somato-dendritic and axonal compartment is regulated. Here, we systematically study mitochondrial motors, including four kinesins, KIF5, KIF17, KIF1, KLP-6, and dynein, and transport regulators in C. elegans PVD neurons. Among all these motors, we found that mitochondrial export from soma to neurites is mainly mediated by KIF5/UNC-116. Interestingly, UNC-116 is especially important for axonal mitochondria, while dynein removes mitochondria from all plus-end dendrites and the axon. We surprisingly found one mitochondrial transport regulator for minus-end dendritic compartment, TRAK-1, and two mitochondrial transport regulators for axonal compartment, CRMP/UNC-33 and JIP3/UNC-16. While JIP3/UNC-16 suppresses axonal mitochondria, CRMP/UNC-33 is critical for axonal mitochondria; nearly no axonal mitochondria present in unc-33 mutants. We showed that UNC-33 is essential for organizing the population of UNC-116-associated microtubule bundles, which are tracks for mitochondrial trafficking. Disarrangement of these tracks impedes mitochondrial transport to the axon. In summary, we identified a compartment-specific transport regulation of mitochondria by UNC-33 through organizing microtubule tracks for different kinesin motors other than microtubule polarity.
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Wisco, Dolora, Eric D. Anderson, Michael C. Chang, Caren Norden, Tatiana Boiko, Heike Fölsch, and Bettina Winckler. "Uncovering multiple axonal targeting pathways in hippocampal neurons." Journal of Cell Biology 162, no. 7 (September 29, 2003): 1317–28. http://dx.doi.org/10.1083/jcb.200307069.
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Neuronal polarity is, at least in part, mediated by the differential sorting of membrane proteins to distinct domains, such as axons and somata/dendrites. We investigated the pathways underlying the subcellular targeting of NgCAM, a cell adhesion molecule residing on the axonal plasma membrane. Following transport of NgCAM kinetically, surprisingly we observed a transient appearance of NgCAM on the somatodendritic plasma membrane. Down-regulation of endocytosis resulted in loss of axonal accumulation of NgCAM, indicating that the axonal localization of NgCAM was dependent on endocytosis. Our data suggest the existence of a dendrite-to-axon transcytotic pathway to achieve axonal accumulation. NgCAM mutants with a point mutation in a crucial cytoplasmic tail motif (YRSL) are unable to access the transcytotic route. Instead, they were found to travel to the axon on a direct route. Therefore, our results suggest that multiple distinct pathways operate in hippocampal neurons to achieve axonal accumulation of membrane proteins.
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Brady, S. T. "Molecular motors and fast axonal transport." Proceedings, annual meeting, Electron Microscopy Society of America 52 (1994): 22–23. http://dx.doi.org/10.1017/s0424820100167846.
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When video microscopy was first used to study fast axonal transport in isolated axoplasm from squid giant axons, a torrent of membrane traffic was seen to move in both directions. Images of membrane bounded organelles (MBOs) moving along individual microtubules (MTs) in axoplasm opened the way for characterization of the microscopic properties of fast axonal transport and led to the characterization of two molecular motors involved in fast axonal transport. The pharmacology of MBO movement ruled out previously identified molecular motors and a biochemical dissection of fast axonal transport in axoplasm demonstrated the existence of a new class of molecular motors. Subsequently, the polypeptides comprising a new class of molecular motor, kinesin, were discovered initiating a new era in the study of molecular motors and intracellular motility.The effects of ATP analogues on fast axonal transport led to dicovery of kinesin. When the nonhydrolyzable ATP analogue, adenylyl 5′-imidodiphosphate (AMP-PNP), was perfused into isolated axoplasm, all MBOs moving in both anterograde and retrograde directions stopped moving and remained attached to MTs. Unlike the effects of AMP-PNP on myosin and dynein, inhibition by AMP-PNP was rapid even in the presence of equimolar ATP, but was reversed by excess ATP.
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Palumbo, Alex, Philipp Grüning, Svenja Kim Landt, Lara Eleen Heckmann, Luisa Bartram, Alessa Pabst, Charlotte Flory, et al. "Deep Learning to Decipher the Progression and Morphology of Axonal Degeneration." Cells 10, no. 10 (September 25, 2021): 2539. http://dx.doi.org/10.3390/cells10102539.
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Axonal degeneration (AxD) is a pathological hallmark of many neurodegenerative diseases. Deciphering the morphological patterns of AxD will help to understand the underlying mechanisms and develop effective therapies. Here, we evaluated the progression of AxD in cortical neurons using a novel microfluidic device together with a deep learning tool that we developed for the enhanced-throughput analysis of AxD on microscopic images. The trained convolutional neural network (CNN) sensitively and specifically segmented the features of AxD including axons, axonal swellings, and axonal fragments. Its performance exceeded that of the human evaluators. In an in vitro model of AxD in hemorrhagic stroke induced by the hemolysis product hemin, we detected a time-dependent degeneration of axons leading to a decrease in axon area, while axonal swelling and fragment areas increased. Axonal swellings preceded axon fragmentation, suggesting that swellings may be reliable predictors of AxD. Using a recurrent neural network (RNN), we identified four morphological patterns of AxD (granular, retraction, swelling, and transport degeneration). These findings indicate a morphological heterogeneity of AxD in hemorrhagic stroke. Our EntireAxon platform enables the systematic analysis of axons and AxD in time-lapse microscopy and unravels a so-far unknown intricacy in which AxD can occur in a disease context.
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Smith, Karen D. B., Erica Peethumnongsin, Han Lin, Hui Zheng, and Robia G. Pautler. "Increased Human Wildtype Tau Attenuates Axonal Transport Deficits Caused by Loss of App in Mouse Models." Magnetic Resonance Insights 4 (January 2010): MRI.S5237. http://dx.doi.org/10.4137/mri.s5237.
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Amyloid precursor protein (APP) is implicated in axonal elongation, synaptic plasticity, and axonal transport. However, the role of APP on axonal transport in conjunction with the microtubule associated protein tau continues to be debated. Here we measured in vivo axonal transport in APP knockout mice with Manganese Enhanced MRI (MEMRI) to determine whether APP is necessary for maintaining normal axonal transport. We also tested how overexpression and mutations of tau affect axonal transport in the presence or absence of APP. In vivo axonal transport reduced significantly in the absence of functional APP. Overexpression of human wildtype tau maintained normal axonal transport and resulted in a transient compensation of axonal transport deficits in the absence of APP. Mutant R406Wtau in combination with the absence of APP compounded axonal transport deficits and these deficits persisted with age. These results indicate that APP is necessary for axonal transport, and overexpression of human wildtype tau can compensate for the absence of APP at an early age.
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Gan, Kathlyn J., and Michael A. Silverman. "Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons." Molecular Biology of the Cell 26, no. 6 (March 15, 2015): 1058–71. http://dx.doi.org/10.1091/mbc.e14-12-1612.
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Disruption of fast axonal transport (FAT) and intracellular Ca2+ dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-β oligomers (AβOs), a causative agent of AD, impair transport of BDNF independent of tau by nonexcitotoxic activation of calcineurin (CaN). Ca2+-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal AβO binding sites are unknown. Here we show that BDNF transport defects in dendrites and axons are induced simultaneously but exhibit different rates of decline. The spatiotemporal progression of FAT impairment correlates with Ca2+ elevation and CaN activation first in dendrites and subsequently in axons. Although many axonal pathologies have been described in AD, studies have primarily focused only on the dendritic effects of AβOs despite compelling reports of presynaptic AβOs in AD models and patients. Indeed, we observe that dendritic CaN activation converges on Ca2+ influx through axonal voltage-gated Ca2+ channels to impair FAT. Finally, FAT defects are prevented by dantrolene, a clinical compound that reduces Ca2+ release from the ER. This work establishes a novel role for Ca2+ dysregulation in BDNF transport disruption and tau-independent Aβ toxicity in early AD.
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Parton, R. G., K. Simons, and C. G. Dotti. "Axonal and dendritic endocytic pathways in cultured neurons." Journal of Cell Biology 119, no. 1 (October 1, 1992): 123–37. http://dx.doi.org/10.1083/jcb.119.1.123.
Full textAbstract:
The endocytic pathways from the axonal and dendritic surfaces of cultured polarized hippocampal neurons were examined. The dendrites and cell body contained extensive networks of tubular early endosomes which received endocytosed markers from the somatodendritic domain. In axons early endosomes were confined to presynaptic terminals and to varicosities. The somatodendritic but not the presynaptic early endosomes were labeled by internalized transferrin. In contrast to early endosomes, late endosomes and lysosomes were shown to be predominantly located in the cell body. Video microscopy was used to follow the transport of internalized markers from the periphery of axons and dendrites back to the cell body. Labeled structures in both domains moved unidirectionally by retrograde fast transport. Axonally transported organelles were sectioned for EM after video microscopic observation and shown to be large multivesicular body-like structures. Similar structures accumulated at the distal side of an axonal lesion. Multivesicular bodies therefore appear to be the major structures mediating transport of endocytosed markers between the nerve terminals and the cell body. Late endocytic structures were also shown to be highly mobile and were observed moving within the cell body and proximal dendritic segments. The results show that the organization of the endosomes differs in the axons and dendrites of cultured rat hippocampal neurons and that the different compartments or stages of the endocytic pathways can be resolved spatially.