Journal articles: 'Axonal loss'

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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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Minzenberg, Michael, Michelle Berkelaar, Garth Bray, and Lisa Mckerracher. "Changes in retinal ganglion cell axons after optic nerve crush: neurofilament expression is not the sole determinant of calibre." Biochemistry and Cell Biology 73, no. 9-10 (September 1, 1995): 599–604. http://dx.doi.org/10.1139/o95-065.

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After injury in the central nervous system of adult mammals, many of the axons that remain attached to their intact cell bodies degenerate and decrease in calibre. To understand this process better, we have investigated the relationship between axonal loss, cell loss, and the time course of changes in axonal calibre. Optic nerves (ONs) were crushed and the numbers and sizes of axons remaining close to the cell bodies (2 mm from the eye) and near the site of the lesion (6 mm from the eye) were determined for nerves examined between 1 week and 3 months after injury. Comparison with the retinal ganglion cell (RGC) counts from the same animals revealed that axonal loss was concomitant with cell body loss for at least the first 2 weeks after injury. However, there was no significant change in the calibre of the surviving neurons until 1 month after injury. Thereafter, the axonal calibre was decreased equally along the ON. No progressive somatofugal atrophy was observed. These decreases in axonal calibre occur much later than the immediate drop in neurofilament (NF) expression that also follows injury. The late effect of injury on axonal calibre suggests that NF expression is not the sole determinant of axon size of the RGC fibers in the ON. Other factors are likely additional contributing factors, such as the decreased rate of axonal transport that would help maintain the axonal neurofilament content.Key words: axonal calibre, axotomy, neuronal cell death, neurofilaments, retinal ganglion cell, optic nerve.

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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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Rao, Mala V., Megan K. Houseweart, Toni L. Williamson, Thomas O. Crawford, Janet Folmer, and Don W. Cleveland. "Neurofilament-dependent Radial Growth of Motor Axons and Axonal Organization of Neurofilaments Does Not Require the Neurofilament Heavy Subunit (NF-H) or Its Phosphorylation." Journal of Cell Biology 143, no. 1 (October 5, 1998): 171–81. http://dx.doi.org/10.1083/jcb.143.1.171.

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Neurofilaments are essential for establishment and maintenance of axonal diameter of large myelinated axons, a property that determines the velocity of electrical signal conduction. One prominent model for how neurofilaments specify axonal growth is that the 660–amino acid, heavily phosphorylated tail domain of neurofilament heavy subunit (NF-H) is responsible for neurofilament-dependent structuring of axoplasm through intra-axonal crossbridging between adjacent neurofilaments or to other axonal structures. To test such a role, homologous recombination was used to generate NF-H–null mice. In peripheral motor and sensory axons, absence of NF-H does not significantly affect the number of neurofilaments or axonal elongation or targeting, but it does affect the efficiency of survival of motor and sensory axons. Loss of NF-H caused only a slight reduction in nearest neighbor spacing of neurofilaments and did not affect neurofilament distribution in either large- or small-diameter motor axons. Since postnatal growth of motor axon caliber continues largely unabated in the absence of NF-H, neither interactions mediated by NF-H nor the extensive phosphorylation of it within myelinated axonal segments are essential features of this growth.

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Haney, C. A., Z. Sahenk, C. Li, V. P. Lemmon, J. Roder, and B. D. Trapp. "Heterophilic Binding of L1 on Unmyelinated Sensory Axons Mediates Schwann Cell Adhesion and Is Required for Axonal Survival." Journal of Cell Biology 146, no. 5 (September 6, 1999): 1173–84. http://dx.doi.org/10.1083/jcb.146.5.1173.

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This study investigated the function of the adhesion molecule L1 in unmyelinated fibers of the peripheral nervous system (PNS) by analysis of L1- deficient mice. We demonstrate that L1 is present on axons and Schwann cells of sensory unmyelinated fibers, but only on Schwann cells of sympathetic unmyelinated fibers. In L1-deficient sensory nerves, Schwann cells formed but failed to retain normal axonal ensheathment. L1-deficient mice had reduced sensory function and loss of unmyelinated axons, while sympathetic unmyelinated axons appeared normal. In nerve transplant studies, loss of axonal-L1, but not Schwann cell-L1, reproduced the L1-deficient phenotype. These data establish that heterophilic axonal-L1 interactions mediate adhesion between unmyelinated sensory axons and Schwann cells, stabilize the polarization of Schwann cell surface membranes, and mediate a trophic effect that assures axonal survival.

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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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Lamoureux, Phillip, Gordon Ruthel, Robert E. Buxbaum, and Steven R. Heidemann. "Mechanical tension can specify axonal fate in hippocampal neurons." Journal of Cell Biology 159, no. 3 (November 4, 2002): 499–508. http://dx.doi.org/10.1083/jcb.200207174.

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Here we asked whether applied mechanical tension would stimulate undifferentiated minor processes of cultured hippocampal neurons to become axons and whether tension could induce a second axon in an already polarized neuron. Experimental tension applied to minor processes produced extensions that demonstrated axonal character, regardless of the presence of an existing axon. Towed neurites showed a high rate of spontaneous growth cone advance and could continue to grow out for 1–3 d after towing. The developmental course of experimental neurites was found to be similar to that of unmanipulated spontaneous axons. Furthermore, the experimentally elongated neurites showed compartmentation of the axonal markers dephospho-tau and L-1 in towed outgrowth after 24 h. Extension of a second axon from an already polarized neuron does not lead to the loss of the spontaneous axon either immediately or after longer term growth. In addition, we were able to initiate neurites de novo that subsequently acquired axonal character even though spontaneous growth cone advance began while the towed neurite was still no longer than its sibling processes. This suggests that tension rather than the achievement of a critical neurite length determined axonal specification.

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Noval, Susana, Inés Contreras, Silvia Muñoz, Celia Oreja-Guevara, Beatriz Manzano, and Gema Rebolleda. "Optical Coherence Tomography in Multiple Sclerosis and Neuromyelitis Optica: An Update." Multiple Sclerosis International 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/472790.

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Optical coherence tomography (OCT) uses light interference patterns to produce a cross-sectional image of the retina. It is capable of measuring the unmyelinated axons of the retinal ganglionar cells as they converge on the optic disc. In a disease like multiple sclerosis (MS), in which axonal loss has been identified as an important cause of sustained disability, it may prove an invaluable tool. OCT has demonstrated that axonal loss occurs after each episode of optic neuritis and that the degree of axonal loss is correlated to visual outcomes. Furthermore, axonal loss occurs in MS even in the absence of inflammatory episodes, and the degree of this loss is correlated with the duration of the disease process, with more thinning as the disease advances and in progressive forms. Thus, OCT retinal nerve fiber layer measurements may represent an objective outcome measure with which to evaluate the effect of treatment.

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Tallantyre, Emma C., Lars Bø, Omar Al-Rawashdeh, Trudy Owens, Chris H. Polman, James S. Lowe, and Nikos Evangelou. "Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis." Multiple Sclerosis Journal 16, no. 4 (March 9, 2010): 406–11. http://dx.doi.org/10.1177/1352458510364992.

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Growing evidence suggests that axonal degeneration rather than demyelination is the pathological substrate underlying chronic, irreversible disability in multiple sclerosis. However, direct evidence linking clinical disability measured in vivo with corresponding post-mortem measures of axonal pathology is lacking. Our objective in this study was to investigate the relationship between motor disability accumulated by patients with multiple sclerosis during life and the degree of axonal loss observed in their descending motor tracts after death. Human spinal cord derived at autopsy from 45 patients with multiple sclerosis was investigated. The medical records of each patient were reviewed by a multiple sclerosis neurologist to determine the degree of motor disability reached before death. Spinal cord sections were stained immunohistochemically. The degree of demyelination and the number of surviving corticospinal tract axons were measured in each patient. Patients who had accumulated higher levels of motor disability prior to death demonstrated fewer surviving corticospinal axons. Motor disability did not correlate with degree of demyelination. This study provides for the first time, direct clinico-pathological evidence that axonal loss is the pathological substrate of established disability in multiple sclerosis.

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Llobet Rosell, Arnau, and Lukas J. Neukomm. "Axon death signalling in Wallerian degeneration among species and in disease." Open Biology 9, no. 8 (August 2019): 190118. http://dx.doi.org/10.1098/rsob.190118.

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Axon loss is a shared feature of nervous systems being challenged in neurological disease, by chemotherapy or mechanical force. Axons take up the vast majority of the neuronal volume, thus numerous axonal intrinsic and glial extrinsic support mechanisms have evolved to promote lifelong axonal survival. Impaired support leads to axon degeneration, yet underlying intrinsic signalling cascades actively promoting the disassembly of axons remain poorly understood in any context, making the development to attenuate axon degeneration challenging. Wallerian degeneration serves as a simple model to study how axons undergo injury-induced axon degeneration (axon death). Severed axons actively execute their own destruction through an evolutionarily conserved axon death signalling cascade. This pathway is also activated in the absence of injury in diseased and challenged nervous systems. Gaining insights into mechanisms underlying axon death signalling could therefore help to define targets to block axon loss. Herein, we summarize features of axon death at the molecular and subcellular level. Recently identified and characterized mediators of axon death signalling are comprehensively discussed in detail, and commonalities and differences across species highlighted. We conclude with a summary of engaged axon death signalling in humans and animal models of neurological conditions. Thus, gaining mechanistic insights into axon death signalling broadens our understanding beyond a simple injury model. It harbours the potential to define targets for therapeutic intervention in a broad range of human axonopathies.

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Perry, V. Hugh, and D. C. Anthony. "Axon damage and repair in multiple sclerosis." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 354, no. 1390 (October 29, 1999): 1641–47. http://dx.doi.org/10.1098/rstb.1999.0509.

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It is well known that within long–standing multiple sclerosis (MS) lesions there is axonal loss but whether it is an early or late event has been more difficult to establish. The use of immunocytochemical methods that reveal axonal end–bulbs is a valuable approach to investigating acute axonal injury in human pathological material. The application of these techniques to multiple sclerosis tissue reveals evidence of axonal injury in acute lesions; the distribution of the end–bulbs in acute and active–chronic lesions is associated with regions of maximal density of infiltrating macrophages. Axon injury within the MS lesion will result in both Wallerian degeneration of the axon and also retrograde degeneration of the cell body. The functional consequences of the axon injury will depend upon numbers of axons injured and the topographical organization of the fibres coursing through the lesion. The molecular mechanisms by which the recruited leucocytes damage or transect the axons are not known. However, investigations in the Wld mutant mouse with very slow Wallerian degeneration demonstrate that axon degeneration is not simply a passive disintegration of the axon but has clear parallels with the active processes of programmed cell death. The presence of early axon injury and the consequences of an ever increasing load of neuronal damage has important implications not only for when therapy should be initiated in MS but also the therapeutic target.

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DeVries, George H. "Cryptic Axonal Antigens and Axonal Loss in Multiple Sclerosis." Neurochemical Research 29, no. 11 (November 2004): 1999–2006. http://dx.doi.org/10.1007/s11064-004-6873-1.

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Garcia, Balañà, Lanuza, Tomàs, Cilleros-Mañé, Just-Borràs, and Tomàs. "Opposed Actions of PKA Isozymes (RI and RII) and PKC Isoforms (cPKCβI and nPKCε) in Neuromuscular Developmental Synapse Elimination." Cells 8, no. 11 (October 23, 2019): 1304. http://dx.doi.org/10.3390/cells8111304.

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Background: During neuromuscular junction (NMJ) development, synapses are produced in excess. By sensing the activity-dependent release of ACh, adenosine, and neurotrophins, presynaptic receptors prompt axonal competition and loss of the unnecessary axons. The receptor action is mediated by synergistic and antagonistic relations when they couple to downstream kinases (mainly protein kinases A and C (PKA and PKC)), which phosphorylate targets involved in axonal disconnection. Here, we directly investigated the involvement of PKA subunits and PKC isoforms in synapse elimination. Methods: Selective PKA and PKC peptide modulators were applied daily to the Levator auris longus (LAL) muscle surface of P5–P8 transgenic B6.Cg-Tg (Thy1-YFP) 16 Jrs/J (and also C57BL/6J) mice, and the number of axons and the postsynaptic receptor cluster morphology were evaluated in P9 NMJ. Results: PKA (PKA-I and PKA-II isozymes) acts at the pre- and postsynaptic sites to delay both axonal elimination and nAChR cluster differentiation, PKC activity promotes both axonal loss (a cPKCβI and nPKCε isoform action), and postsynaptic nAChR cluster maturation (a possible role for PKCθ). Moreover, PKC-induced changes in axon number indirectly influence postsynaptic maturation. Conclusions: PKC and PKA have opposed actions, which suggests that changes in the balance of these kinases may play a major role in the mechanism of developmental synapse elimination.

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Kidd, G. J., J. W. Heath, B. D. Trapp, and P. R. Dunkley. "Myelin sheath survival after guanethidine-induced axonal degeneration." Journal of Cell Biology 116, no. 2 (January 15, 1992): 395–403. http://dx.doi.org/10.1083/jcb.116.2.395.

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Membrane-membrane interactions between axons and Schwann cells are required for initial myelin formation in the peripheral nervous system. However, recent studies of double myelination in sympathetic nerve have indicated that myelin sheaths continue to exist after complete loss of axonal contact (Kidd, G. J., and J. W. Heath. 1988. J. Neurocytol. 17:245-261). This suggests that myelin maintenance may be regulated either by diffusible axonal factors or by nonaxonal mechanisms. To test these hypotheses, axons involved in double myelination in the rat superior cervical ganglion were destroyed by chronic guanethidine treatment. Guanethidine-induced sympathectomy resulted in a Wallerian-like pattern of myelin degeneration within 10 d. In doubly myelinated configurations the axon, inner myelin sheath (which lies in contact with the axon), and approximately 75% of outer myelin sheaths broke down by this time. Degenerating outer sheaths were not found at later periods. It is probably that outer sheaths that degenerated were only partially displaced from the axon at the commencement of guanethidine treatment. In contrast, analysis of serial sections showed that completely displaced outer internodes remained ultrastructurally intact. These internodes survived degeneration of the axon and inner sheath, and during the later time points (2-6 wk) they enclosed only connective tissue elements and reorganized Schwann cells/processes. Axonal regeneration was not observed within surviving outer internodes. We therefore conclude that myelin maintenance in the superior cervical ganglion is not dependent on direct axonal contact or diffusible axonal factors. In addition, physical association of Schwann cells with the degenerating axon may be an important factor in precipitating myelin breakdown during Wallerian degeneration.

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Gresle, Melissa M., Yaou Liu, Trevor J. Kilpatrick, Dennis Kemper, Qi-Zhu Wu, Bing Hu, Qing-Ling Fu, et al. "Blocking LINGO-1 in vivo reduces degeneration and enhances regeneration of the optic nerve." Multiple Sclerosis Journal - Experimental, Translational and Clinical 2 (January 1, 2016): 205521731664170. http://dx.doi.org/10.1177/2055217316641704.

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Background Two ongoing phase II clinical trials (RENEW and SYNERGY) have been developed to test the efficacy of anti-LINGO-1 antibodies in acute optic neuritis and relapsing forms of multiple sclerosis, respectively. Across a range of experimental models, LINGO-1 has been found to inhibit neuron and oligodendrocyte survival, axon regeneration, and (re)myelination. The therapeutic effects of anti-LINGO-1 antibodies on optic nerve axonal loss and regeneration have not yet been investigated. Objective In this series of studies we investigate if LINGO-1 antibodies can prevent acute inflammatory axonal loss, and promote axonal regeneration after injury in rodent optic nerves. Methods The effects of anti-LINGO-1 antibody on optic nerve axonal damage were assessed using rodent myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (EAE), and its effects on axonal regeneration were assessed in optic nerve crush injury models. Results In the optic nerve, anti-LINGO-1 antibody therapy was associated with improved optic nerve parallel diffusivity measures on MRI in mice with EAE and reduced axonal loss in rat EAE. Both anti-LINGO-1 antibody therapy and the genetic deletion of LINGO-1 reduced nerve crush-induced axonal degeneration and enhanced axonal regeneration. Conclusion These data demonstrate that LINGO-1 blockade is associated with axonal protection and regeneration in the injured optic nerve.

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Boia, Raquel, Noelia Ruzafa, Inês Dinis Aires, Xandra Pereiro, António Francisco Ambrósio, Elena Vecino, and Ana Raquel Santiago. "Neuroprotective Strategies for Retinal Ganglion Cell Degeneration: Current Status and Challenges Ahead." International Journal of Molecular Sciences 21, no. 7 (March 25, 2020): 2262. http://dx.doi.org/10.3390/ijms21072262.

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The retinal ganglion cells (RGCs) are the output cells of the retina into the brain. In mammals, these cells are not able to regenerate their axons after optic nerve injury, leaving the patients with optic neuropathies with permanent visual loss. An effective RGCs-directed therapy could provide a beneficial effect to prevent the progression of the disease. Axonal injury leads to the functional loss of RGCs and subsequently induces neuronal death, and axonal regeneration would be essential to restore the neuronal connectivity, and to reestablish the function of the visual system. The manipulation of several intrinsic and extrinsic factors has been proposed in order to stimulate axonal regeneration and functional repairing of axonal connections in the visual pathway. However, there is a missing point in the process since, until now, there is no therapeutic strategy directed to promote axonal regeneration of RGCs as a therapeutic approach for optic neuropathies.

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Aburegeba, Zina, Jie Pan, and Harald Hutter. "Mutations in the Spliceosome Component prp-6 and Overexpression of cdh-5 Suppress Axon Guidance Defects of cdh-4 Mutants in Caenorhabditis elegans." Neuroscience Insights 17 (January 2022): 263310552211233. http://dx.doi.org/10.1177/26331055221123346.

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During nervous system development, axons must navigate to specific target areas. In Caenorhabditis elegans, the cadherin CDH-4 is required for ventral nerve cord axonal navigation, and dorsal nerve cord fasciculation. How CDH-4 mediates axon navigation and fasciculation is currently unknown. To identify genes acting together with cdh-4, we isolated mutants suppressing the axon guidance defects of cdh-4 mutants. These suppressors showed partial suppression of axonal defects in the dorsal and ventral nerve cords seen in cdh-4 mutants. We identified one suppressor gene, prp-6, which encodes a component of the spliceosome. Complete loss-of-function alleles of prp-6 are lethal, suggesting that the mutation isolated in our suppressor screen is a partial loss-of-function allele. A previous study found that RNAi-induced suppression of prp-6 leads to changes in the expression of several 100 genes including the cadherin cdh-5. We found that overexpression of cdh-5 mimics the suppression seen in prp-6 mutants, suggesting that CDH-5 can partially compensate for the loss of CDH-4.

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Lambiri, Darius W., and Leonard A. Levin. "Modeling Reactive Oxygen Species-Induced Axonal Loss in Leber Hereditary Optic Neuropathy." Biomolecules 12, no. 10 (October 2, 2022): 1411. http://dx.doi.org/10.3390/biom12101411.

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Leber hereditary optic neuropathy (LHON) is a rare syndrome that results in vision loss. A necessary but not sufficient condition for its onset is the existence of known mitochondrial DNA mutations that affect complex I biomolecular structure. Cybrids with LHON mutations generate higher rates of reactive oxygen species (ROS). This study models how ROS, particularly H2O2, could signal and execute the axonal degeneration process that underlies LHON. We modeled and explored several hypotheses regarding the influence of H2O2 on the dynamics of propagation of axonal degeneration in LHON. Zonal oxidative stress, corresponding to H2O2 gradients, correlated with the morphology of injury exhibited in the LHON pathology. If the axonal membrane is highly permeable to H2O2 and oxidative stress induces larger production of H2O2, small injuries could trigger cascading failures of neighboring axons. The cellular interdependence created by H2O2 diffusion, and the gradients created by tissue variations in H2O2 production and scavenging, result in injury patterns and surviving axonal loss distributions similar to LHON tissue samples. Specifically, axonal degeneration starts in the temporal optic nerve, where larger groups of small diameter fibers are located and propagates from that region. These findings correlate well with clinical observations of central loss of visual field, visual acuity, and color vision in LHON, and may serve as an in silico platform for modeling the mechanism of action for new therapeutics.

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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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Kikuchi, Tateki. "Circular breakdown of neural networks due to loss of deubiquitinating enzyme (UCH-L1) in gracile axonal dystrophy (gad) mouse." AIMS Molecular Science 8, no. 4 (2021): 311–24. http://dx.doi.org/10.3934/molsci.2021024.

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<abstract> Gracile axonal dystrophy (gad) mouse shows tremor, ataxia and muscular atrophy of hind limbs from about 80-days of age. These clinical features become progressively severe to death. Pathological examination reveals that main and early axonal degeneration exists in a long ascending nervous tract in dorsal column of the spinal cord: gracile nucleus and fascicules. Similar lesions are seen in axonal terminals of peripheral sensory (muscle spindles) and motor endplates. Most striking features of axonal dystrophy are “dying-back” axonal degeneration with partial swellings (“spheroids” in matured type) which come to be most frequently in gracile nucleus, followed by in order of gracile fasciculus of cervical, thoracic and lumber cord levels. Immunocytochemical increase of glial fibrillary acidic protein (GFAP) and substance P (SP) is seen in reactive astrocytes and degenerating axons. Likewise, amyloid precursor protein (APP) and amyloid β-protein (AβP) activity become positive in axons and astrocytes along ascending tract. Moreover, ubiquitin-positive dot-like structures accumulate in gracile nucleus, spinocerebellar tract, and cerebellum in <italic>gad</italic> mice after 9th-week old. Ubiquitinated structures are localized in spheroids with a larger diameter than normal. The <italic>gad</italic> mutation is caused by an in-frame deletion including exon 7 and 8 of <italic>UCH-L1</italic> gene, encoding the ubiquitin c-terminal hydrolase (UCH) isozyme (UCH-L1) selectively expressed in nervous system and testis/ovary. The <italic>gad</italic> allele encodes a truncated UCH-L1 lacking a segment of 42 amino acids containing catalytic site. The evaluation as mouse models for Parkinson's and Alzheimer's diseases and the collapse of synapse-axon circulation around central nervous system from peripheral nervous system are discussed. </abstract>

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Das Sarma, Jayasri. "A Mechanism of Virus-Induced Demyelination." Interdisciplinary Perspectives on Infectious Diseases 2010 (2010): 1–28. http://dx.doi.org/10.1155/2010/109239.

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Myelin forms an insulating sheath surrounding axons in the central and peripheral nervous systems and is essential for rapid propagation of neuronal action potentials. Demyelination is an acquired disorder in which normally formed myelin degenerates, exposing axons to the extracellular environment. The result is dysfunction of normal neuron-to-neuron communication and in many cases, varying degrees of axonal degeneration. Numerous central nervous system demyelinating disorders exist, including multiple sclerosis. Although demyelination is the major manifestation of most of the demyelinating diseases, recent studies have clearly documented concomitant axonal loss to varying degrees resulting in long-term disability. Axonal injury may occur secondary to myelin damage (outside-in model) or myelin damage may occur secondary to axonal injury (inside-out model). Viral induced demyelination models, has provided unique imminent into the cellular mechanisms of myelin destruction. They illustrate mechanisms of viral persistence, including latent infections, virus reactivation and viral-induced tissue damage. These studies have also provided excellent paradigms to study the interactions between the immune system and the central nervous system (CNS). In this review we will discuss potential cellular and molecular mechanism of central nervous system axonal loss and demyelination in a viral induced mouse model of multiple sclerosis.

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Sherry, Tessa, Ava Handley, Hannah R. Nicholas, and Roger Pocock. "Harmonization of L1CAM expression facilitates axon outgrowth and guidance of a motor neuron." Development 147, no. 20 (September 29, 2020): dev193805. http://dx.doi.org/10.1242/dev.193805.

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ABSTRACTBrain development requires precise regulation of axon outgrowth, guidance and termination by multiple signaling and adhesion molecules. How the expression of these neurodevelopmental regulators is transcriptionally controlled is poorly understood. The Caenorhabditis elegans SMD motor neurons terminate axon outgrowth upon sexual maturity and partially retract their axons during early adulthood. Here we show that C-terminal binding protein 1 (CTBP-1), a transcriptional corepressor, is required for correct SMD axonal development. Loss of CTBP-1 causes multiple defects in SMD axon development: premature outgrowth, defective guidance, delayed termination and absence of retraction. CTBP-1 controls SMD axon guidance by repressing the expression of SAX-7, an L1 cell adhesion molecule (L1CAM). CTBP-1-regulated repression is crucial because deregulated SAX-7/L1CAM causes severely aberrant SMD axons. We found that axonal defects caused by deregulated SAX-7/L1CAM are dependent on a distinct L1CAM, called LAD-2, which itself plays a parallel role in SMD axon guidance. Our results reveal that harmonization of L1CAM expression controls the development and maturation of a single neuron.

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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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Nadal, Laura, Neus Garcia, Erica Hurtado, Anna Simó, Marta Tomàs, Maria Angel Lanuza, Victor Cilleros, and Josep Maria Tomàs. "Synergistic Action of Presynaptic Muscarinic Acetylcholine Receptors and Adenosine Receptors in Developmental Axonal Competition at the Neuromuscular Junction." Developmental Neuroscience 38, no. 6 (2016): 407–19. http://dx.doi.org/10.1159/000458437.

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The development of the nervous system involves the initial overproduction of synapses, which promotes connectivity. Hebbian competition between axons with different activities leads to the loss of roughly half of the overproduced elements and this refines connectivity. We used quantitative immunohistochemistry to investigate, in the postnatal day 7 (P7) to P9 neuromuscular junctions, the involvement of muscarinic receptors (muscarinic acetylcholine autoreceptors and the M1, M2, and M4 subtypes) and adenosine receptors (A1 and A2A subtypes) in the control of axonal elimination after the mouse levator auris longus muscle had been exposed to selective antagonists in vivo. In a previous study we analyzed the role of each of the individual receptors. Here we investigate the additive or occlusive effects of their inhibitors and thus the existence of synergistic activity between the receptors. The main results show that the A2A, M1, M4, and A1 receptors (in this order of ability) delayed axonal elimination at P7. M4 produces some occlusion of the M1 pathway and some addition to the A1 pathway, which suggests that they cooperate. M2 receptors may modulate (by allowing a permissive action) the other receptors, mainly M4 and A1. The continued action of these receptors (now including M2 but not M4) finally promotes axonal loss at P9. All 4 receptors (M2, M1, A1, and A2A, in this order of ability) are necessary. The M4 receptor (which in itself does not affect axon loss) seems to modulate the other receptors. We found a synergistic action between the M1, A1, and A2A receptors, which show an additive effect, whereas the potent M2 effect is largely independent of the other receptors (though can be modulated by M4). At P9, there is a full mutual dependence between the A1 and A2A receptors in regulating axon loss. In summary, postnatal axonal elimination is a regulated multireceptor mechanism that involves the cooperation of several muscarinic and adenosine receptor subtypes.

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McSharry, Carolyn. "Axonal loss linked to MS disability." Nature Reviews Neurology 6, no. 6 (June 2010): 300. http://dx.doi.org/10.1038/nrneurol.2010.63.

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Yan, Ying, Matthew D. Wood, Amy M. Moore, Alison K. Snyder-Warwick, Daniel A. Hunter, Piyaraj Newton, Louis Poppler, Thomas H. Tung, Philip J. Johnson, and Susan E. Mackinnon. "Robust Axonal Regeneration in a Mouse Vascularized Composite Allotransplant Model Undergoing Delayed Tissue Rejection." HAND 11, no. 4 (July 8, 2016): 456–63. http://dx.doi.org/10.1177/1558944715620791.

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Background: Nerve regeneration in vascularized composite allotransplantation (VCA) is not well understood. Allogeneic transplant models experience complete loss of nerve tissue and axonal regeneration without immunosuppressive therapy. The purpose of this study was to determine the impact of incomplete immunosuppression on nerve regeneration. Methods: In this study, transgenic mice (4 groups in total) with endogenous fluorescent protein expression in axons (Thy1-YFP) and Schwann cells (S100-GFP) were used to evaluate axonal regeneration and Schwann cell (SC) migration in orthotopic-limb VCA models with incomplete immunosuppression using Tacrolimus (FK506). Survival and complication rates were assessed to determine the extent of tissue rejection. Nerve regeneration was assessed using serial imaging of axonal progression and SC migration and viability. Histomorphometry quantified the extent of axonal regeneration. Results: Incomplete immunosuppression with FK506 resulted in delayed rejection of skin, muscle, tendon, and bone in the transplanted limb. In contrast, the nerve demonstrated robust axonal regeneration and SC viability based on strong fluorescent protein expression by SCs and axons in transgenic donors and recipients. Total myelinated axon numbers measured at 8 weeks were comparable in all VCA groups and not statistically different from the syngeneic donor control group. Conclusions: Our data suggest that nerve and SCs are much weaker antigens compared with skin, muscle, tendon, and bone in VCA. To our knowledge, this study is the first to prove the weak antigenicity of nerve tissue in the orthotopic VCA mouse model.

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Yan, Rui, Jessica C. Page, and Riyi Shi. "Acrolein-mediated conduction loss is partially restored by K+ channel blockers." Journal of Neurophysiology 115, no. 2 (February 1, 2016): 701–10. http://dx.doi.org/10.1152/jn.00467.2015.

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Acrolein-mediated myelin damage is thought to be a critical mechanism leading to conduction failure following neurotrauma and neurodegenerative diseases. The exposure and activation of juxtaparanodal voltage-gated K+ channels due to myelin damage leads to conduction block, and K+ channel blockers have long been studied as a means for restoring axonal conduction in spinal cord injury (SCI) and multiple sclerosis (MS). In this study, we have found that 100 μM K+ channel blockers 4-aminopyridine-3-methanol (4-AP-3-MeOH), and to a lesser degree 4-aminopyridine (4-AP), can significantly restore compound action potential (CAP) conduction in spinal cord tissue following acrolein-mediated myelin damage using a well-established ex vivo SCI model. In addition, 4-AP-3-MeOH can effectively restore CAP conduction in acrolein-damaged axons with a range of concentrations from 0.1 to 100 μM. We have also shown that while both compounds at 100 μM showed no preference of small- and large-caliber axons when restoring CAP conduction, 4-AP-3-MeOH, unlike 4-AP, is able to augment CAP amplitude while causing little change in axonal responsiveness measured in refractory periods and response to repetitive stimuli. In a prior study, we show that 4-AP-3-MeOH was able to functionally rescue mechanically injured axons. In this investigation, we conclude that 4-AP-3-MeOH is an effective K+ channel blocker in restoring axonal conduction following both primary (physical) and secondary (chemical) insults. These findings also suggest that 4-AP-3-MeOH is a viable alternative of 4-AP for treating myelin damage and improving function following central nervous system trauma and neurodegenerative diseases.

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Klistorner, Samuel, Michael H. Barnett, Jakob Wasserthal, Con Yiannikas, Joshua Barton, John Parratt, Yuyi You, Stuart L. Graham, and Alexander Klistorner. "Differentiating axonal loss and demyelination in chronic MS lesions: A novel approach using single streamline diffusivity analysis." PLOS ONE 16, no. 1 (January 6, 2021): e0244766. http://dx.doi.org/10.1371/journal.pone.0244766.

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We describe a new single-streamline based approach to analyse diffusivity within chronic MS lesions. We used the proposed method to examine diffusivity profiles in 30 patients with relapsing multiple sclerosis and observed a significant increase of both RD and AD within the lesion core (0.38+/-0.09 μm2/ms and 0.30+/-0.12 μm2/ms respectively, p<0.0001 for both) that gradually and symmetrically diminished away from the lesion. T1-hypointensity derived axonal loss correlated highly with ΔAD (r = 0.82, p<0.0001), but moderately with ΔRD (r = 0.60, p<0.0001). Furthermore, the trendline of the ΔAD vs axonal loss intersected both axes at zero indicating close agreement between two measures in assessing the degree of axonal loss. Conversely, the trendline of the ΔRD function demonstrated a high positive value at the zero level of axonal loss, suggesting that even lesions with preserved axonal content exhibit a significant increase of RD. There was also a significant negative correlation between the level of preferential RD increase (ΔRD-ΔAD) in the lesion core and the degree of axonal damage (r = -0.62, p<0.001), indicating that ΔRD dominates in cases with milder axonal loss. Modelling diffusivity changes in the core of chronic MS lesions based on the direct proportionality of ΔAD with axonal loss and the proposed dual nature of ΔRD yielded results that were strikingly similar to the experimental data. Evaluation of lesions in a sizable cohort of MS patients using the proposed method supports the use of ΔAD as a marker of axonal loss; and the notion that demyelination and axonal loss independently contribute to the increase of RD in chronic MS lesions. The work highlights the importance of selecting appropriate patient cohorts for clinical trials of pro-remyelinating and neuroprotective therapeutics.

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Wang, Jack T., Zachary A. Medress, and Ben A. Barres. "Axon degeneration: Molecular mechanisms of a self-destruction pathway." Journal of Cell Biology 196, no. 1 (January 9, 2012): 7–18. http://dx.doi.org/10.1083/jcb.201108111.

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Axon degeneration is a characteristic event in many neurodegenerative conditions including stroke, glaucoma, and motor neuropathies. However, the molecular pathways that regulate this process remain unclear. Axon loss in chronic neurodegenerative diseases share many morphological features with those in acute injuries, and expression of the Wallerian degeneration slow (WldS) transgene delays nerve degeneration in both events, indicating a common mechanism of axonal self-destruction in traumatic injuries and degenerative diseases. A proposed model of axon degeneration is that nerve insults lead to impaired delivery or expression of a local axonal survival factor, which results in increased intra-axonal calcium levels and calcium-dependent cytoskeletal breakdown.

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Kitaoka, Yasushi, Yasunari Munemasa, Yasuhiro Hayashi, Junko Kuribayashi, Natsuko Koseki, Kaori Kojima, Toshio Kumai, and Satoki Ueno. "Axonal Protection by 17β-Estradiol through Thioredoxin-1 in Tumor Necrosis Factor-Induced Optic Neuropathy." Endocrinology 152, no. 7 (May 17, 2011): 2775–85. http://dx.doi.org/10.1210/en.2011-0046.

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Axonal degeneration often leads to the death of neuronal cell bodies. Previous studies demonstrated the substantial protective role of 17β-estradiol (E2) in several types of neuron. However, most studies examined cell body protection, and the role of 17β-E2 in axonal degeneration of retinal ganglion cells (RGC) remains unclear. In this study, we showed the presence of thioredoxin-1 (Trx1) in the optic nerve axons and found that the levels of Trx1 protein were significantly decreased in isolated RGC and the optic nerve after intravitreal injection of TNF, which was shown previously to induce optic nerve degeneration and subsequent loss of RGC. These changes were concomitant with disorganization of the microtubules with neurofilament accumulation, which were blocked by 17β-E2 implantation. 17β-E2 treatment also totally abolished TNF-induced decreases in Trx1 protein levels in isolated RGC and the optic nerve. The induction of Trx1 by 17β-E2 in the optic nerve was significantly inhibited by simultaneous injection of Trx1 small interfering RNA (siRNA) with TNF. Up-regulation of Trx1 by 17β-E2 in RGC-5 cells was prevented by Trx1 siRNA treatment. 17β-E2 significantly prevented TNF-induced axonal loss, and this axonal-protective effect was inhibited by intravitreal injection of Trx1 siRNA. This finding was also supported by the quantification of microtubules and neurofilaments. These results suggest that a Trx1 decrease in RGC bodies and their axons may be associated with TNF-induced optic nerve axonal degeneration. Axonal protection by 17β-E2 may be related to its regulatory effect on Trx1 induction.

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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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Brochier, Camille, James I. Jones, Dianna E. Willis, and Brett Langley. "Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration." Proceedings of the National Academy of Sciences 112, no. 49 (November 23, 2015): 15220–25. http://dx.doi.org/10.1073/pnas.1509754112.

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Therapeutic options for the restoration of neurological functions after acute axonal injury are severely limited. In addition to limiting neuronal loss, effective treatments face the challenge of restoring axonal growth within an injury environment where inhibitory molecules from damaged myelin and activated astrocytes act as molecular and physical barriers. Overcoming these barriers to permit axon growth is critical for the development of any repair strategy in the central nervous system. Here, we identify poly(ADP-ribose) polymerase 1 (PARP1) as a previously unidentified and critical mediator of multiple growth-inhibitory signals. We show that exposure of neurons to growth-limiting molecules—such as myelin-derived Nogo and myelin-associated glycoprotein—or reactive astrocyte-produced chondroitin sulfate proteoglycans activates PARP1, resulting in the accumulation of poly(ADP-ribose) in the cell body and axon and limited axonal growth. Accordingly, we find that pharmacological inhibition or genetic loss of PARP1 markedly facilitates axon regeneration over nonpermissive substrates. Together, our findings provide critical insights into the molecular mechanisms of axon growth inhibition and identify PARP1 as an effective target to promote axon regeneration.

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Wong, P. C., J. Marszalek, T. O. Crawford, Z. Xu, S. T. Hsieh, J. W. Griffin, and D. W. Cleveland. "Increasing neurofilament subunit NF-M expression reduces axonal NF-H, inhibits radial growth, and results in neurofilamentous accumulation in motor neurons." Journal of Cell Biology 130, no. 6 (September 15, 1995): 1413–22. http://dx.doi.org/10.1083/jcb.130.6.1413.

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The carboxy-terminal tail domains of neurofilament subunits neurofilament NF-M and NF-H have been postulated to be responsible for the modulation of axonal caliber. To test how subunit composition affects caliber, transgenic mice were generated to increase axonal NF-M. Total neurofilament subunit content in motor and sensory axons remained essentially unchanged, but increases in NF-M were offset by proportionate decreases in both NF-H and axonal cross-sectional area. Increase in NF-M did not affect the level of phosphorylation of NF-H. This indicates that (a) in vivo NF-H and NF-M compete either for coassembly with a limiting amount of NF-L or as substrates for axonal transport, and (b) NF-H abundance is a primary determinant of axonal caliber. Despite inhibition of radial growth, increase in NF-M and reduction in axonal NF-H did not affect nearest neighbor spacing between neurofilaments, indicating that cross-bridging between nearest neighbors does not play a crucial role in radial growth. Increase in NF-M did not result in an overt phenotype or neuronal loss, although filamentous swellings in perikarya and proximal axons of motor neurons were frequently found.

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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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Leitzen, Eva, Wen Jin, Vanessa Herder, Andreas Beineke, Suliman Elmarabet, Wolfgang Baumgärtner, and Florian Hansmann. "Comparison of Reported Spinal Cord Lesions in Progressive Multiple Sclerosis with Theiler’s Murine Encephalomyelitis Virus Induced Demyelinating Disease." International Journal of Molecular Sciences 20, no. 4 (February 25, 2019): 989. http://dx.doi.org/10.3390/ijms20040989.

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Background: Spinal cord (SC) lesions in Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) resemble important features of brain lesions in progressive multiple sclerosis (MS) including inflammation, demyelination, and axonal damage. The aim of the present study was a comparison of SC lesions in MS and TMEV-IDD focusing on spatial and temporal distribution of demyelination, inflammation, SC atrophy (SCA), and axonal degeneration/loss in major descending motor pathways. Methods: TMEV and mock-infected mice were investigated clinically once a week. SC tissue was collected at 42, 98, 147, and 196 days post infection, and investigated using hematoxylin and eosin (HE) staining, immunohistochemistry targeting myelin basic protein (demyelination), Mac3 (microglia/macrophages), phosphorylated neurofilaments (axonal damage) and transmission electron microscopy. Results: Demyelination prevailed in SC white matter in TMEV-IDD, contrasting a predominant gray matter involvement in MS. TMEV-infected mice revealed a significant loss of axons similar to MS. Ultrastructural analysis in TMEV-IDD revealed denuded axons, degenerative myelin changes, axonal degeneration, as well as remyelination. SCA is a consistent finding in the SC of MS patients and was also detected at a late time point in TMEV-IDD. Conclusion: This comparative study further indicates the suitability of TMEV-IDD as animal model also for the investigation of progressive SC lesions in MS.

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Prado, Mario B. Jr, and Karen Joy B. Adiao. "Mixed IgG and IgM anti-GM1 ganglioside antibody positive multifocal motor neuropathy with severe secondary axonal loss in a Filipino female." Neurology Asia 27, no. 4 (December 2022): 1041–45. http://dx.doi.org/10.54029/2022fjs.

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Approximately 40% of patients with multifocal motor neuropathy had anti-GM1 IgM antibodies, while only 1 out of 88 patients had anti-GM1 IgG antibodies. Unlike its predominantly demyelinating IgM counterpart, the anti-GM1 IgG antibody is often seen in the axonal variant of Guillain Barre syndrome. As it affects axons, it is also associated with worse prognosis. We report here a 58-year-old woman who was admitted for 3 months history of progressive asymmetric weakness, initially involving the right-hand extensors, eventually affecting the contralateral side and the lower extremities. The electrodiagnostic examination revealed multifocal pure motor demyelinating neuropathy with severe axonal loss. On nerve ultrasound, the axons were small in non-compressive areas. The extremely elevated anti-GM1 IgM titer (1:51,200, nv<1:800) was consistent with the diagnosis of MMN. Her anti-GM1 IgG antibodies (1: 12,800, nv<1:800) was also elevated. In conclusion, the presence of concomitant anti-GM IgG and anti-GM1 IgM may lead to an MMN with more severe axonal loss.

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Lomoio, Selene, Rachel Willen, WonHee Kim, Kevin Z. Ho, Edward K. Robinson, Dmitry Prokopenko, Matthew E. Kennedy, Rudolph E. Tanzi, and Giuseppina Tesco. "Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer’s disease trigger BACE1 accumulation in axonal swellings." Science Translational Medicine 12, no. 570 (November 18, 2020): eaba1871. http://dx.doi.org/10.1126/scitranslmed.aba1871.

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Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer’s disease (AD) pathogenesis. Little is known about the mechanisms underlying this initial sign of the pathology. This study proves that Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) loss of function, due to Gga3 genetic deletion or a GGA3 rare variant that cosegregates with late-onset AD, disrupts the axonal trafficking of the β-site APP-cleaving enzyme 1 (BACE1) resulting in its accumulation in axonal swellings in cultured neurons and in vivo. We show that BACE pharmacological inhibition ameliorates BACE1 axonal trafficking and diminishes axonal dystrophies in Gga3 null neurons in vitro and in vivo. These data indicate that axonal accumulation of BACE1 engendered by GGA3 loss of function results in local toxicity leading to axonopathy. Gga3 deletion exacerbates axonal dystrophies in a mouse model of AD before β-amyloid (Aβ) deposition. Our study strongly supports a role for GGA3 in AD pathogenesis, where GGA3 loss of function triggers BACE1 axonal accumulation independently of extracellular Aβ, and initiates a cascade of events leading to the axonal damage distinctive of the early stage of AD.

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Lucas, F. R., R. G. Goold, P. R. Gordon-Weeks, and P. C. Salinas. "Inhibition of GSK-3beta leading to the loss of phosphorylated MAP-1B is an early event in axonal remodelling induced by WNT-7a or lithium." Journal of Cell Science 111, no. 10 (May 15, 1998): 1351–61. http://dx.doi.org/10.1242/jcs.111.10.1351.

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WNT-7a induces axonal spreading and branching in developing cerebellar granule neurons. This effect is mediated through the inhibition of GSK-3beta, a serine/threonine kinase and a component of the WNT pathway. Lithium, an inhibitor of GSK-3beta, mimics WNT-7a in granule cells. Here we examined further the effect of GSK-3beta inhibition on cytoskeletal re-organisation. Lithium induces axonal spreading and increases growth cone area and perimeter. This effect is associated with the absence or reduction of stable microtubules in spread areas. Lithium induces the loss of a phosphorylated form of MAP-1B, a microtubule associated protein involved in axonal outgrowth. Down-regulation of the phosphorylated MAP-1B, MAP-1B-P, from axonal processes occurs before axonal remodelling is evident. In vitro phosphorylation assays show that MAP-1B-P is generated by direct phosphorylation of MAP-1B by GSK-3beta. WNT-7a, like lithium, also leads to loss of MAP-1B-P from spread axons and growth cones. Our data suggest that WNT-7a and lithium induce changes in microtubule dynamics by inhibiting GSK-3beta which in turn lead to changes in the phosphorylation of MAP-1B. These findings suggest a novel role for GSK-3beta and WNTs in axonal remodelling and identify MAP-1B as a new target for GSK-3beta and WNT.

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Uncini, Antonino, and Lucio Santoro. "The electrophysiology of axonal neuropathies: More than just evidence of axonal loss." Clinical Neurophysiology 131, no. 10 (October 2020): 2367–74. http://dx.doi.org/10.1016/j.clinph.2020.07.014.

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Saatman, Kathryn E., Babak Abai, Ashley Grosvenor, Christian K. Vorwerk, Douglas H. Smith, and David F. Meaney. "Traumatic Axonal Injury Results in Biphasic Calpain Activation and Retrograde Transport Impairment in Mice." Journal of Cerebral Blood Flow & Metabolism 23, no. 1 (January 2003): 34–42. http://dx.doi.org/10.1097/01.wcb.0000035040.10031.b0.

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Traumatic axonal injury (TAI) is one of the most important pathologies associated with closed head injury, and contributes to ensuing morbidity. The authors evaluated the potential role of calpains in TAI using a new model of optic nerve stretch injury in mice. Male C57BL/6 mice were anesthetized, surgically prepared, and subjected to a 2.0-mm optic nerve stretch injury (n = 34) or sham injury (n = 18). At various intervals up to 2 weeks after injury, optic nerves were examined for neurofilament proteins and calpain-mediated spectrin breakdown products using immunohistochemistry. In addition, fluorescent tracer was injected into the superior colliculi of mice 1 day before they were killed, to investigate the integrity of retrograde axonal transport to the retina. Optic nerve stretch injury resulted in persistent disruption of retrograde axonal transport by day 1, progressive accumulation and dephosphorylation of neurofilament protein in swollen and disconnected axons, and subsequent loss of neurofilament protein in degenerating axons at day 14. Calpains were transiently activated in intact axons in the first minutes to hours after stretch injury. A second stage of calpain-mediated proteolysis was observed at 4 days in axonal swellings, bulbs, and fragments. These data suggest that early calpain activation may contribute to progressive intra-axonal structural damage, whereas delayed calpain activation may be associated with axonal degeneration.

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Langford, Clair, and Ann Jervie Sefton. "The relative time course of axonal loss from the optic nerve of the developing guinea pig is consistent with that of other mammals." Visual Neuroscience 9, no. 6 (December 1992): 555–64. http://dx.doi.org/10.1017/s0952523800001796.

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AbstractThe relative timing of a number of events during the development of the visual system has recently been suggested to be consistent across a number of mammalian species (Dreher & Robinson, 1988). Some conflicting reports, however, had suggested that the precocial guinea pig might represent an exception to the generalized scheme. A quantitative study was thus carried out on the development of the optic nerve and retina of the guinea pig. Consistent with the prediction of a stable relative time course of mammalian visual development, axons and growth cones were found in the optic stalk from the 24th postconceptional day (40% of the period from conception to eye opening —the cecal period), the peak number of axons was observed on the 32nd postconceptional day (56% of the cecal period), and the phase of rapid axonal loss extended to the 39th and 42nd postconceptional days (68–74% of the cecal period). The number of axons in the adult optic nerve (117,000) represented about 37% of the peak number of axons. Additional observations indicated that during development of the optic nerve the mean axonal diameter increased approximately threefold from 0.31 μm to 1.06 μm. As in other mammals studied so far, myelination was first noted after the period of rapid axonal loss and continued until in the adult 97% of axons were found to be myelinated. In the retina, the presence of pyknotic profiles in the ganglion cell layers extends throughout the periods of loss of the optic nerve axons. Finally, the presence of pyknotic profiles in the amacrine sublayer suggest that in the guinea pig, as in other mammalian species, there is a loss of displaced amacrine cells as well as ganglion cells from the ganglion cell layer.

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Lorenzo, Damaris Nadia, Alexandra Badea, Jonathan Davis, Janell Hostettler, Jiang He, Guisheng Zhong, Xiaowei Zhuang, and Vann Bennett. "A PIK3C3–Ankyrin-B–Dynactin pathway promotes axonal growth and multiorganelle transport." Journal of Cell Biology 207, no. 6 (December 22, 2014): 735–52. http://dx.doi.org/10.1083/jcb.201407063.

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Axon growth requires long-range transport of organelles, but how these cargoes recruit their motors and how their traffic is regulated are not fully resolved. In this paper, we identify a new pathway based on the class III PI3-kinase (PIK3C3), ankyrin-B (AnkB), and dynactin, which promotes fast axonal transport of synaptic vesicles, mitochondria, endosomes, and lysosomes. We show that dynactin associates with cargo through AnkB interactions with both the dynactin subunit p62 and phosphatidylinositol 3-phosphate (PtdIns(3)P) lipids generated by PIK3C3. AnkB knockout resulted in shortened axon tracts and marked reduction in membrane association of dynactin and dynein, whereas it did not affect the organization of spectrin–actin axonal rings imaged by 3D-STORM. Loss of AnkB or of its linkages to either p62 or PtdIns(3)P or loss of PIK3C3 all impaired organelle transport and particularly retrograde transport in hippocampal neurons. Our results establish new functional relationships between PIK3C3, dynactin, and AnkB that together promote axonal transport of organelles and are required for normal axon length.

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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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Friedmann, Drew, Albert Pun, Eliza L. Adams, Jan H. Lui, Justus M. Kebschull, Sophie M. Grutzner, Caitlin Castagnola, Marc Tessier-Lavigne, and Liqun Luo. "Mapping mesoscale axonal projections in the mouse brain using a 3D convolutional network." Proceedings of the National Academy of Sciences 117, no. 20 (May 1, 2020): 11068–75. http://dx.doi.org/10.1073/pnas.1918465117.

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The projection targets of a neuronal population are a key feature of its anatomical characteristics. Historically, tissue sectioning, confocal microscopy, and manual scoring of specific regions of interest have been used to generate coarse summaries of mesoscale projectomes. We present here TrailMap, a three-dimensional (3D) convolutional network for extracting axonal projections from intact cleared mouse brains imaged by light-sheet microscopy. TrailMap allows region-based quantification of total axon content in large and complex 3D structures after registration to a standard reference atlas. The identification of axonal structures as thin as one voxel benefits from data augmentation but also requires a loss function that tolerates errors in annotation. A network trained with volumes of serotonergic axons in all major brain regions can be generalized to map and quantify axons from thalamocortical, deep cerebellar, and cortical projection neurons, validating transfer learning as a tool to adapt the model to novel categories of axonal morphology. Speed of training, ease of use, and accuracy improve over existing tools without a need for specialized computing hardware. Given the recent emphasis on genetically and functionally defining cell types in neural circuit analysis, TrailMap will facilitate automated extraction and quantification of axons from these specific cell types at the scale of the entire mouse brain, an essential component of deciphering their connectivity.

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Forte, Michael, Bruce G. Gold, Gail Marracci, Priya Chaudhary, Emy Basso, Dustin Johnsen, Xiaolin Yu, Jonathan Fowlkes, Paolo Bernardi, and Dennis Bourdette. "Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis." Proceedings of the National Academy of Sciences 104, no. 18 (April 26, 2007): 7558–63. http://dx.doi.org/10.1073/pnas.0702228104.

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Multiple sclerosis (MS) is the leading cause of neurological disability in young adults, affecting some two million people worldwide. Traditionally, MS has been considered a chronic, inflammatory disorder of the central white matter in which ensuing demyelination results in physical disability [Frohman EM, Racke MK, Raine CS (2006) N Engl J Med 354:942–955]. More recently, MS has become increasingly viewed as a neurodegenerative disorder in which neuronal loss, axonal injury, and atrophy of the CNS lead to permanent neurological and clinical disability. Although axonal pathology and loss in MS has been recognized for >100 years, very little is known about the underlying molecular mechanisms. Progressive axonal loss in MS may stem from a cascade of ionic imbalances initiated by inflammation, leading to mitochondrial dysfunction and energetic deficits that result in mitochondrial and cellular Ca2+ overload. In a murine disease model, experimental autoimmune encephalomyelitis (EAE) mice lacking cyclophilin D (CyPD), a key regulator of the mitochondrial permeability transition pore (PTP), developed EAE, but unlike WT mice, they partially recovered. Examination of the spinal cords of CyPD-knockout mice revealed a striking preservation of axons, despite a similar extent of inflammation. Furthermore, neurons prepared from CyPD-knockout animals were resistant to reactive oxygen and nitrogen species thought to mediate axonal damage in EAE and MS, and brain mitochondria lacking CyPD sequestered substantially higher levels of Ca2+. Our results directly implicate pathological activation of the mitochondrial PTP in the axonal damage occurring during MS and identify CyPD, as well as the PTP, as a potential target for MS neuroprotective therapies.

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Porrello, Emanuela, Cristina Rivellini, Giorgia Dina, Daniela Triolo, Ubaldo Del Carro, Daniela Ungaro, Martina Panattoni, et al. "Jab1 regulates Schwann cell proliferation and axonal sorting through p27." Journal of Experimental Medicine 211, no. 1 (December 16, 2013): 29–43. http://dx.doi.org/10.1084/jem.20130720.

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Axonal sorting is a crucial event in nerve formation and requires proper Schwann cell proliferation, differentiation, and contact with axons. Any defect in axonal sorting results in dysmyelinating peripheral neuropathies. Evidence from mouse models shows that axonal sorting is regulated by laminin211– and, possibly, neuregulin 1 (Nrg1)–derived signals. However, how these signals are integrated in Schwann cells is largely unknown. We now report that the nuclear Jun activation domain–binding protein 1 (Jab1) may transduce laminin211 signals to regulate Schwann cell number and differentiation during axonal sorting. Mice with inactivation of Jab1 in Schwann cells develop a dysmyelinating neuropathy with axonal sorting defects. Loss of Jab1 increases p27 levels in Schwann cells, which causes defective cell cycle progression and aberrant differentiation. Genetic down-regulation of p27 levels in Jab1-null mice restores Schwann cell number, differentiation, and axonal sorting and rescues the dysmyelinating neuropathy. Thus, Jab1 constitutes a regulatory molecule that integrates laminin211 signals in Schwann cells to govern cell cycle, cell number, and differentiation. Finally, Jab1 may constitute a key molecule in the pathogenesis of dysmyelinating neuropathies.

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Levin, Leonard A. "Axonal loss and neuroprotection in optic neuropathies." Canadian Journal of Ophthalmology 42, no. 3 (2007): 403–8. http://dx.doi.org/10.3129/i07-046.

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MATTHEWS, P. M. "Axonal loss and demyelation in multiple sclerosis." Journal of Neurology, Neurosurgery & Psychiatry 67, no. 6 (December 1, 1999): 708–9. http://dx.doi.org/10.1136/jnnp.67.6.708.

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Walker, Kimberly L., Hee Kwang Yoo, Jayanthi Undamatla, and Ben G. Szaro. "Loss of Neurofilaments Alters Axonal Growth Dynamics." Journal of Neuroscience 21, no. 24 (December 15, 2001): 9655–66. http://dx.doi.org/10.1523/jneurosci.21-24-09655.2001.

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Esfahani, Mohammad Riazi, Zahra Alami Harandi, Morteza Movasat, Mojgan Nikdel, Mohsen Adelpour, Arezo Momeni, Hamid Merat, and Masoud Aghsaei Fard. "Memantine for axonal loss of optic neuritis." Graefe's Archive for Clinical and Experimental Ophthalmology 250, no. 6 (December 16, 2011): 863–69. http://dx.doi.org/10.1007/s00417-011-1894-3.

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Journal articles on the topic 'Axonal loss'

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