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Karel Svoboda - One of the best experts on this subject based on the ideXlab platform.
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cell type specific structural plasticity of Axonal branches and boutons in the adult neocortex
Neuron, 2006Co-Authors: Vincenzo De Paola, Sen Song, Pico Caroni, Graham Knott, Anthony Holtmaat, Linda Wilbrecht, Karel SvobodaAbstract:Summary We imaged axons in layer (L) 1 of the mouse barrel cortex in vivo. Axons from thalamus and L2/3/5, or L6 pyramidal cells were identified based on their distinct morphologies. Their branching patterns and sizes were stable over times of months. However, Axonal branches and boutons displayed cell type-specific rearrangements. Structural plasticity in thalamocortical afferents was mostly due to elongation and retraction of branches (range, 1–150 μm over 4 days; ∼5% of total Axonal length), while the majority of boutons persisted for up to 9 months (persistence over 1 month ∼85%). In contrast, L6 axon terminaux boutons were highly plastic (persistence over 1 month ∼40 %), and other intracortical axon boutons showed intermediate levels of plasticity. Retrospective electron microscopy revealed that new boutons make synapses. Our data suggest that structural plasticity of Axonal branches and boutons contributes to the remodeling of specific functional circuits.
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Cell type-specific structural plasticity of Axonal branches and boutons in the adult neocortex
Neuron, 2006Co-Authors: Vincenzo De Paola, Sen Song, Pico Caroni, Graham Knott, Anthony Holtmaat, Linda Wilbrecht, Karel SvobodaAbstract:We imaged axons in layer (L) 1 of the mouse barrel cortex in vivo. Axons from thalamus and L2/3/5, or L6 pyramidal cells were identified based on their distinct morphologies. Their branching patterns and sizes were stable over times of months. However, Axonal branches and boutons displayed cell type-specific rearrangements. Structural plasticity in thalamocortical afferents was mostly due to elongation and retraction of branches (range, 1-150 μm over 4 days; ∼5% of total Axonal length), while the majority of boutons persisted for up to 9 months (persistence over 1 month ∼85%). In contrast, L6 axon terminaux boutons were highly plastic (persistence over 1 month ∼40 %), and other intracortical axon boutons showed intermediate levels of plasticity. Retrospective electron microscopy revealed that new boutons make synapses. Our data suggest that structural plasticity of Axonal branches and boutons contributes to the remodeling of specific functional circuits. ©2006 Elsevier Inc.
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diverse modes of axon elaboration in the developing neocortex
PLOS Biology, 2005Co-Authors: Vincenzo De Paola, Pico Caroni, Carlos Porteracailliau, Robby M Weimer, Karel SvobodaAbstract:The development of Axonal arbors is a critical step in the establishment of precise neural circuits, but relatively little is known about the mechanisms of Axonal elaboration in the neocortex. We used in vivo two-photon time-lapse microscopy to image axons in the neocortex of green fluorescent protein-transgenic mice over the first 3 wk of postnatal development. This period spans the elaboration of thalamocortical (TC) and Cajal-Retzius (CR) axons and cortical synaptogenesis. Layer 1 collaterals of TC and CR axons were imaged repeatedly over time scales ranging from minutes up to days, and their growth and pruning were analyzed. The structure and dynamics of TC and CR axons differed profoundly. Branches of TC axons terminated in small, bulbous growth cones, while CR axon branch tips had large growth cones with numerous long filopodia. TC axons grew rapidly in straight paths, with frequent interstitial branch additions, while CR axons grew more slowly along tortuous paths. For both types of axon, new branches appeared at interstitial sites along the axon shaft and did not involve growth cone splitting. Pruning occurred via retraction of small axon branches (tens of microns, at both CR and TC axons) or degeneration of large portions of the arbor (hundreds of microns, for TC axons only). The balance between growth and retraction favored overall growth, but only by a slight margin. Given the identical layer 1 territory upon which CR and TC axons grow, the differences in their structure and dynamics likely reflect distinct intrinsic growth programs for axons of long projection neurons versus local interneurons.
Vincenzo De Paola - One of the best experts on this subject based on the ideXlab platform.
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cell type specific structural plasticity of Axonal branches and boutons in the adult neocortex
Neuron, 2006Co-Authors: Vincenzo De Paola, Sen Song, Pico Caroni, Graham Knott, Anthony Holtmaat, Linda Wilbrecht, Karel SvobodaAbstract:Summary We imaged axons in layer (L) 1 of the mouse barrel cortex in vivo. Axons from thalamus and L2/3/5, or L6 pyramidal cells were identified based on their distinct morphologies. Their branching patterns and sizes were stable over times of months. However, Axonal branches and boutons displayed cell type-specific rearrangements. Structural plasticity in thalamocortical afferents was mostly due to elongation and retraction of branches (range, 1–150 μm over 4 days; ∼5% of total Axonal length), while the majority of boutons persisted for up to 9 months (persistence over 1 month ∼85%). In contrast, L6 axon terminaux boutons were highly plastic (persistence over 1 month ∼40 %), and other intracortical axon boutons showed intermediate levels of plasticity. Retrospective electron microscopy revealed that new boutons make synapses. Our data suggest that structural plasticity of Axonal branches and boutons contributes to the remodeling of specific functional circuits.
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Cell type-specific structural plasticity of Axonal branches and boutons in the adult neocortex
Neuron, 2006Co-Authors: Vincenzo De Paola, Sen Song, Pico Caroni, Graham Knott, Anthony Holtmaat, Linda Wilbrecht, Karel SvobodaAbstract:We imaged axons in layer (L) 1 of the mouse barrel cortex in vivo. Axons from thalamus and L2/3/5, or L6 pyramidal cells were identified based on their distinct morphologies. Their branching patterns and sizes were stable over times of months. However, Axonal branches and boutons displayed cell type-specific rearrangements. Structural plasticity in thalamocortical afferents was mostly due to elongation and retraction of branches (range, 1-150 μm over 4 days; ∼5% of total Axonal length), while the majority of boutons persisted for up to 9 months (persistence over 1 month ∼85%). In contrast, L6 axon terminaux boutons were highly plastic (persistence over 1 month ∼40 %), and other intracortical axon boutons showed intermediate levels of plasticity. Retrospective electron microscopy revealed that new boutons make synapses. Our data suggest that structural plasticity of Axonal branches and boutons contributes to the remodeling of specific functional circuits. ©2006 Elsevier Inc.
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diverse modes of axon elaboration in the developing neocortex
PLOS Biology, 2005Co-Authors: Vincenzo De Paola, Pico Caroni, Carlos Porteracailliau, Robby M Weimer, Karel SvobodaAbstract:The development of Axonal arbors is a critical step in the establishment of precise neural circuits, but relatively little is known about the mechanisms of Axonal elaboration in the neocortex. We used in vivo two-photon time-lapse microscopy to image axons in the neocortex of green fluorescent protein-transgenic mice over the first 3 wk of postnatal development. This period spans the elaboration of thalamocortical (TC) and Cajal-Retzius (CR) axons and cortical synaptogenesis. Layer 1 collaterals of TC and CR axons were imaged repeatedly over time scales ranging from minutes up to days, and their growth and pruning were analyzed. The structure and dynamics of TC and CR axons differed profoundly. Branches of TC axons terminated in small, bulbous growth cones, while CR axon branch tips had large growth cones with numerous long filopodia. TC axons grew rapidly in straight paths, with frequent interstitial branch additions, while CR axons grew more slowly along tortuous paths. For both types of axon, new branches appeared at interstitial sites along the axon shaft and did not involve growth cone splitting. Pruning occurred via retraction of small axon branches (tens of microns, at both CR and TC axons) or degeneration of large portions of the arbor (hundreds of microns, for TC axons only). The balance between growth and retraction favored overall growth, but only by a slight margin. Given the identical layer 1 territory upon which CR and TC axons grow, the differences in their structure and dynamics likely reflect distinct intrinsic growth programs for axons of long projection neurons versus local interneurons.
J C Vickers - One of the best experts on this subject based on the ideXlab platform.
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microtubule dependent processes precede pathological calcium influx in excitotoxin induced axon degeneration
Journal of Neurochemistry, 2020Co-Authors: Na Tia, J C Vickers, Kelsey Hanso, A Canty, Anna E. KingAbstract:Axon degeneration and Axonal loss is a feature of neurodegenerative disease and injury and occurs via programmed pathways that are distinct from cell death pathways. While the pathways of Axonal loss following axon severing are well described, less is known about Axonal loss following other neurodegenerative insults. Here we use primary mouse cortical neuron cultures grown in compartmentalized chambers to investigate the role of calcium in the degeneration of axons that occurs following a somal insult by the excitotoxin kainic acid. Calcium influx has been implicated in both excitotoxicity and axon degeneration mechanisms, however the link between a somal insult and Axonal calcium increase is unclear. Live imaging of axons demonstrated that pharmacologically preventing intracellular calcium increases through the endoplasmic reticulum or mitochondria significantly (p < 0.05) reduced axon degeneration. Live calcium-imaging with the Ca2+ indicator Fluo-4 demonstrated that kainic acid exposure to the soma resulted in a rapid, and transient, increase in calcium in the axon, which occured even at low kainic acid concentrations that do not cause axon degeneration within 24 hours. However, this calcium transient was followed by a gradual increase in Axonal calcium, which was associated with Axonal loss. Furthermore, treatment with a range of doses of the microtubule stabilizing drug taxol, which protects against axon fragmentation in this model, prevented this gradual calcium increase, suggesting that the intra-Axonal calcium changes are downstream of microtubule associated events. Biochemical analysis of taxol treated neurons demonstrated a shift in microtubule post-translational modifications, with a significant (p < 0.05) increase in acetylated tubulin and a significant (p < 0.05) decrease in tyrosinated tubulin, suggestive of a more stable microtubule pool. Together our results suggest that Axonal degeneration following excitotoxicity is dependent on an increase in Axonal calcium, which is downstream of a microtubule dependent event.
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Microtubule-dependent processes precede pathological calcium influx in excitotoxin-induced axon degeneration
'Wiley', 2019Co-Authors: Tia N, J C Vickers, Kelsey Hanso, A Canty, Ae KingAbstract:Axon degeneration and Axonal loss is a feature of neurodegenerative disease and injury and occurs via programmed pathways that are distinct from cell death pathways. While the pathways of Axonal loss following axon severing are well described, less is known about Axonal loss following other neurodegenerative insults. Here we use primary mouse cortical neuron cultures grown in compartmentalized chambers to investigate the role of calcium in the degeneration of axons that occurs following a somal insult by the excitotoxin kainic acid. Calcium influx has been implicated in both excitotoxicity and axon degeneration mechanisms, however the link between a somal insult and Axonal calcium increase is unclear. Live imaging of axons demonstrated that pharmacologically preventing intracellular calcium increases through the endoplasmic reticulum or mitochondria significantly (p 2+ indicator Fluo-4 demonstrated that kainic acid exposure to the soma resulted in a rapid, and transient, increase in calcium in the axon, which occured even at low kainic acid concentrations that do not cause axon degeneration within 24 hours. However, this calcium transient was followed by a gradual increase in Axonal calcium, which was associated with Axonal loss. Furthermore, treatment with a range of doses of the microtubule stabilizing drug taxol, which protects against axon fragmentation in this model, prevented this gradual calcium increase, suggesting that the intra-Axonal calcium changes are downstream of microtubule associated events. Biochemical analysis of taxol treated neurons demonstrated a shift in microtubule post-translational modifications, with a significant (p p < 0.05) decrease in tyrosinated tubulin, suggestive of a more stable microtubule pool. Together our results suggest that Axonal degeneration following excitotoxicity is dependent on an increase in Axonal calcium, which is downstream of a microtubule dependent event
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excitotoxin induced caspase 3 activation and microtubule disintegration in axons is inhibited by taxol
Acta neuropathologica communications, 2013Co-Authors: Anna E. King, Katherine A. Southam, Justi Dittma, J C VickersAbstract:Background: Axon degeneration, a key pathological event in many neurodegenerative diseases and injury, can be induced by somatodendritic excitotoxin exposure. It is currently unclear, however, whether excitotoxin-induced axon degeneration is mechanistically similar to Wallerian degeneration, which occurs following axon transection, but does not involve Axonal caspase activation. Results: We have used mouse primary cortical neurons at 9 days in vitro, in a compartmented culture model that allows separation of the axon from the soma, to examine the pathological cascade of excitotoxin-induced axon degeneration. Excitotoxicity induced by chronic exposure to kainic acid, resulted in Axonal fragmentation, which was associated with activation of caspase-3 in the Axonal compartment. To examine the role of microtubules in these events, the microtubule-stabilizing agent, taxol, was added to either the Axonal or somatodendritic compartment. Our results demonstrated that microtubule stabilization of axons resulted in a significant reduction in the number of fragmented axons following excitotoxin exposure. Interestingly, taxol exposure to either the somatodendritic or Axonal compartment resulted in reduced caspase-3 activation in axons, suggesting that caspase activation is a downstream event of microtubule destabilization and involves signalling from the cell soma. Conclusion: These data suggest that excitotoxin-induced axon degeneration shows some mechanistic differences to Wallerian degeneration, and that microtubule stabilization may assist in protecting nerve cells from excitotoxic effects.
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chronic excitotoxin induced axon degeneration in a compartmented neuronal culture model
Asn Neuro, 2012Co-Authors: K A Hosie, Anna E. King, J C Vickers, Catherine A Lizzard, T C DicksoAbstract:Glutamate excitotoxicity is a major pathogenic process implicated in many neurodegenerative conditions, including AD (Alzheimer's disease) and following traumatic brain injury. Occurring predominantly from over-stimulation of ionotropic glutamate receptors located along dendrites, excitotoxic Axonal degeneration may also occur in white matter tracts. Recent identification of Axonal glutamate receptor subunits within Axonal nanocomplexes raises the possibility of direct excitotoxic effects on axons. Individual neuronal responses to excitotoxicity are highly dependent on the complement of glutamate receptors expressed by the cell, and the localization of the functional receptors. To enable isolation of distal axons and targeted excitotoxicity, murine cortical neuron cultures were prepared in compartmented microfluidic devices, such that distal axons were isolated from neuronal cell bodies. Within the compartmented culture system, cortical neurons developed to relative maturity at 11 DIV (days in vitro) as demonstrated by the formation of dendritic spines and clustering of the presynaptic protein synaptophysin. The isolated distal axons retained growth cone structures in the absence of synaptic targets, and expressed glutamate receptor subunits. Glutamate treatment (100 μM) to the cell body chamber resulted in widespread degeneration within this chamber and degeneration of distal axons in the other chamber. Glutamate application to the distal axon chamber triggered a lesser degree of Axonal degeneration without degenerative changes in the untreated somal chamber. These data indicate that in addition to current mechanisms of indirect Axonal excitotoxicity, the distal axon may be a primary target for excitotoxicity in neurodegenerative conditions.
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mild Axonal stretch injury in vitro induces a progressive series of neurofilament alterations ultimately leading to delayed axotomy
Journal of Neurotrauma, 2005Co-Authors: Roger S Chung, Jerome A Staal, Graeme H Mccormack, T C Dickson, Mark A Cozens, J A Chuckowree, Marian C Quilty, J C VickersAbstract:We report a new model of transient Axonal stretch injury involving pressurized fluid deflection of bundles of axons, resulting in a transient 1–6% increase in original axon length to investigate the slow progression of Axonal alterations that are characteristic of diffuse Axonal injury (DAI). We found no discernable difference in axon bundle morphology or cytoskeletal neurofilament protein arrangement between unstretched and stretched Axonal bundles at 24 h post-injury. However, by 48 h post-injury, there was a stereotypical response of stretched axons involving characteristic neurofilament alterations that bear similarities to in vivo neuronal responses associated with DAI that have been reported previously. For instance, neurofilament protein immunoreactivity (SMI-312) was increased in axons contained within 51% of all injured axon bundles at 48 h compared to surrounding unstretched axon bundles, suggestive of neurofilament compaction. Furthermore, Axonal bundle derangement occurred in 25% of injured ax...
Douglas H Smith - One of the best experts on this subject based on the ideXlab platform.
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newfound sex differences in Axonal structure underlie differential outcomes from in vitro traumatic Axonal injury
Experimental Neurology, 2018Co-Authors: Jeanpierre Dolle, Andrew Jaye, Stewart A Anderson, Hossein Ahmadzadeh, Vivek B Shenoy, Douglas H SmithAbstract:Abstract Since traumatic Axonal injury (TAI) is implicated as a prominent pathology of concussion, we examined potential sex differences in axon structure and responses to TAI. Rat and human neurons were used to develop micropatterned axon tracts in vitro that were genetically either male or female. Ultrastructural analysis revealed for the first time that female axons were consistently smaller with fewer microtubules than male axons. Computational modeling of TAI showed that these structural differences place microtubules in female axons at greater risk of failure during trauma under the same applied loads than in male axons. Likewise, in an in vitro model of TAI, dynamic stretch-injury to axon tracts induced greater pathophysiology of female axons than male axons, including more extensive undulation formations resulting from mechanical breaking of microtubules, and greater calcium influx shortly after the same level of injury. At 24 h post-injury, female axons exhibited significantly more swellings and greater loss of calcium signaling function than male axons. Accordingly, sexual dimorphism of axon structure in the brain may also contribute to more extensive Axonal pathology in females compared to males exposed to the same mechanical injury.
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partial interruption of Axonal transport due to microtubule breakage accounts for the formation of periodic varicosities after traumatic Axonal injury
Experimental Neurology, 2012Co-Authors: Min D Tangschomer, Peter W Baas, Victoria E Johnson, William Stewart, Douglas H SmithAbstract:Due to their viscoelastic nature, white matter axons are susceptible to damage by high strain rates produced during traumatic brain injury (TBI). Indeed, diffuse Axonal injury (DAI) is one of the most common features of TBI, characterized by the hallmark pathological profiles of Axonal bulbs at disconnected terminal ends of axons and periodic swellings along axons, known as "varicosities." Although transport interruption underlies Axonal bulb formation, it is unclear how varicosities arise, with multiple sites accumulating transported materials along one axon. Recently, Axonal microtubules have been found to physically break during dynamic stretch injury of cortical axons in vitro. Here, the same in vitro model was used in parallel with histopathological analyses of human brains acquired acutely following TBI to examine the potential role of mechanical microtubule damage in varicosity formation post-trauma. Transmission electron microscopy (TEM) following in vitro stretch injury revealed periodic breaks of individual microtubules along axons that regionally corresponded with undulations in axon morphology. However, typically less than a third of microtubules were broken in any region of an axon. Within hours, these sites of microtubule breaks evolved into periodic swellings. This suggests Axonal transport may be halted along one broken microtubule, yet can proceed through the same region via other intact microtubules. Similar Axonal undulations and varicosities were observed following TBI in humans, suggesting primary microtubule failure may also be a feature of DAI. These data indicate a novel mechanism of mechanical microtubule damage leading to partial transport interruption and varicosity formation in traumatic Axonal injury.
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mechanical breaking of microtubules in axons during dynamic stretch injury underlies delayed elasticity microtubule disassembly and axon degeneration
The FASEB Journal, 2010Co-Authors: Min D Tangschomer, Ankur R Patel, Peter W Baas, Douglas H SmithAbstract:Little is known about which components of the Axonal cytoskeleton might break during rapid mechanical deformation, such as occurs in traumatic brain injury. Here, we micropatterned neuronal cell cultures on silicone membranes to induce dynamic stretch exclusively of axon fascicles. After stretch, undulating distortions formed along the axons that gradually relaxed back to a straight orientation, demonstrating a delayed elastic response. Subsequently, swellings developed, leading to degeneration of almost all axons by 24 h. Stabilizing the microtubules with taxol maintained the undulating geometry after injury but greatly reduced axon degeneration. Conversely, destabilizing microtubules with nocodazole prevented undulations but greatly increased the rate of axon loss. Ultrastructural analyses of axons postinjury revealed immediate breakage and buckling of microtubules in axon undulations and progressive loss of microtubules. Collectively, these data suggest that dynamic stretch of axons induces direct mechanical failure at specific points along microtubules. This microtubule disorganization impedes normal relaxation of the axons, resulting in undulations. However, this physical damage also triggers progressive disassembly of the microtubules around the breakage points. While the disintegration of microtubules allows delayed recovery of the “normal” straight axon morphology, it comes at a great cost by interrupting Axonal transport, leading to Axonal swelling and degeneration.—Tang-Schomer, M. D., Patel, A. R,, Baas, P. W., Smith, D. H. Mechanical breaking of microtubules in axons during dynamic stretch injury underlies delayed elasticity, microtubule disassembly, and axon degeneration.
Michael P Coleman - One of the best experts on this subject based on the ideXlab platform.
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subcellular localization determines the stability and axon protective capacity of axon survival factor nmnat2
PLOS Biology, 2013Co-Authors: Stefan Milde, Jonathan Gilley, Michael P ColemanAbstract:Axons require a constant supply of the labile axon survival factor Nmnat2 from their cell bodies to avoid spontaneous axon degeneration. Here we investigate the mechanism of fast Axonal transport of Nmnat2 and its site of action for axon maintenance. Using dual-colour live-cell imaging of Axonal transport in SCG primary culture neurons, we find that Nmnat2 is bidirectionally trafficked in axons together with markers of the trans-Golgi network and synaptic vesicles. In contrast, there is little co-migration with mitochondria, lysosomes, and active zone precursor vesicles. Residues encoded by the small, centrally located exon 6 are necessary and sufficient for stable membrane association and vesicular Axonal transport of Nmnat2. Within this sequence, a double cysteine palmitoylation motif shared with GAP43 and surrounding basic residues are all required for efficient palmitoylation and stable association with Axonal transport vesicles. Interestingly, however, disrupting this membrane association increases the ability of Axonally localized Nmnat2 to preserve transected neurites in primary culture, while re-targeting the strongly protective cytosolic mutants back to membranes abolishes this increase. Larger deletions within the central domain including exon 6 further enhance Nmnat2 axon protective capacity to levels that exceed that of the slow Wallerian degeneration protein, WldS. The mechanism underlying the increase in axon protection appears to involve an increased half-life of the cytosolic forms, suggesting a role for palmitoylation and membrane attachment in Nmnat2 turnover. We conclude that Nmnat2 activity supports axon survival through a site of action distinct from Nmnat2 transport vesicles and that protein stability, a key determinant of axon protection, is enhanced by mutations that disrupt palmitoylation and dissociate Nmnat2 from these vesicles.
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mechanisms of Axonal spheroid formation in central nervous system wallerian degeneration
Journal of Neuropathology and Experimental Neurology, 2010Co-Authors: Bogdan Beirowski, Antal Nogradi, Elisabetta Babetto, Guillermo Garciaalias, Michael P ColemanAbstract:Wallerian degeneration of the CNS is accompanied by Axonal dystrophy or swelling. To understand the mechanisms by which swellings arise, we studied their spatiotemporal dynamics, ultrastructure, composition, and the conditions that affect their formationin vivo and ex vivo. In contrast to peripheral nerve axons, lesioned optic nerve (ON) axons in vivo developed focal swellings asynchronously within 6 hours, long before there is any axon fragmentation. Axons in ON, spinal cord dorsal column, and corpus callosum all showed marked gradients with more swellings in proximal regions of their distal stumps early after lesion. Time-lapse imaging of a validated ex vivo system showed that multiple focal swellings arise after around 1 hour close to the injury site, followed by anterograde wave-like progression on continuous ON axon stumps. Swellings were largely stable but occasionally seemed to fuse with neighboring swellings. Their ultrastructural appearances resembled disease-associated spheroids. Although accumulation of Axonal markers suggested transport deficits, large accumulations of mitochondria were not observed. Early swelling formation was decreased in Wld S gene-expressing rodents and by removing extracellular calcium. Several pharmacologic agents that inhibit axon loss in vitro and/or in vivo also prevented early formation of Axonal spheroids in acute ON explants. Because Axonal swellings are hallmarks of many neurodegenerative conditions, these data suggest that they are a manifestation of Wallerian-like degeneration in some cases. Thus, Wallerian-like degeneration may be a more common component mechanism in CNS diseases than previously thought.
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axon degeneration mechanisms commonality amid diversity
Nature Reviews Neuroscience, 2005Co-Authors: Michael P ColemanAbstract:A wide range of insults can trigger axon degeneration, and axons respond with diverse morphology, topology and speed. However, recent genetic, immunochemical, morphological and pharmacological investigations point to convergent degeneration mechanisms. The principal convergence points - poor Axonal transport, mitochondrial dysfunction and an increase in intra-Axonal calcium - have been identified by rescuing axons with the slow Wallerian degeneration gene (Wld(S)) and studies with blockers of sodium or calcium influx. By understanding how the pathways fit together, we can combine our knowledge of mechanisms, and potentially also treatment strategies, from different Axonal disorders.