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Hand Clinics Aug 2013Peripheral nerve injuries are common conditions, with broad-ranging groups of symptoms depending on the severity and nerves involved. Although much knowledge exists on... (Review)
Review
Peripheral nerve injuries are common conditions, with broad-ranging groups of symptoms depending on the severity and nerves involved. Although much knowledge exists on the mechanisms of injury and regeneration, reliable treatments that ensure full functional recovery are scarce. This review aims to summarize various ways these injuries are classified in light of decades of research on peripheral nerve injury and regeneration.
Topics: Animals; Axons; Cells, Cultured; Humans; Macrophages; Models, Animal; Models, Biological; Nerve Compression Syndromes; Nerve Fibers; Nerve Growth Factors; Nerve Regeneration; Neurons; Peripheral Nerve Injuries; Peripheral Nerves; Schwann Cells; Wallerian Degeneration
PubMed: 23895713
DOI: 10.1016/j.hcl.2013.04.002 -
ELife Dec 2022Upon trauma, the adult murine peripheral nervous system (PNS) displays a remarkable degree of spontaneous anatomical and functional regeneration. To explore extrinsic...
Upon trauma, the adult murine peripheral nervous system (PNS) displays a remarkable degree of spontaneous anatomical and functional regeneration. To explore extrinsic mechanisms of neural repair, we carried out single-cell analysis of naïve mouse sciatic nerve, peripheral blood mononuclear cells, and crushed sciatic nerves at 1 day, 3 days, and 7 days following injury. During the first week, monocytes and macrophages (Mo/Mac) rapidly accumulate in the injured nerve and undergo extensive metabolic reprogramming. Proinflammatory Mo/Mac with a high glycolytic flux dominate the early injury response and rapidly give way to inflammation resolving Mac, programmed toward oxidative phosphorylation. Nerve crush injury causes partial leakiness of the blood-nerve barrier, proliferation of endoneurial and perineurial stromal cells, and entry of opsonizing serum proteins. Micro-dissection of the nerve injury site and distal nerve, followed by single-cell RNA-sequencing, identified distinct immune compartments, triggered by mechanical nerve wounding and Wallerian degeneration, respectively. This finding was independently confirmed with mice, in which Wallerian degeneration is greatly delayed. Experiments with chimeric mice showed that wildtype immune cells readily enter the injury site in mice, but are sparse in the distal nerve, except for Mo. We used CellChat to explore intercellular communications in the naïve and injured PNS and report on hundreds of ligand-receptor interactions. Our longitudinal analysis represents a new resource for neural tissue regeneration, reveals location- specific immune microenvironments, and reports on large intercellular communication networks. To facilitate mining of scRNAseq datasets, we generated the injured sciatic nerve atlas (iSNAT): https://cdb-rshiny.med.umich.edu/Giger_iSNAT/.
Topics: Mice; Animals; Wallerian Degeneration; Leukocytes, Mononuclear; Sciatic Nerve; Nerve Degeneration; Nerve Crush; Peripheral Nerve Injuries; Nerve Regeneration; Cytoskeletal Proteins; Armadillo Domain Proteins
PubMed: 36515985
DOI: 10.7554/eLife.80881 -
Free Neuropathology Jan 2023This review highlights ten important advances in the neuromuscular disease field that were reported in 2022. As with prior updates in this article series, the...
This review highlights ten important advances in the neuromuscular disease field that were reported in 2022. As with prior updates in this article series, the overarching topics include (i) advances in understanding of fundamental neuromuscular biology; (ii) new / emerging diseases; (iii) advances in understanding of disease etiology and pathogenesis; (iv) diagnostic advances; and (v) therapeutic advances. Within this general framework, the individual disease entities that are discussed in more detail include neuromuscular complications of COVID-19 (another look at the topic first covered in the 2021 and 2022 reviews), DNAJB4-associated myopathy, NMNAT2-deficient hereditary axonal neuropathy, Guillain-Barré syndrome, sporadic inclusion body myositis, and amyotrophic lateral sclerosis. In addition, the review highlights a few other advances (including new insights into mechanisms of fiber maturation during muscle regeneration and fiber rebuilding following reinnervation, improved genetic testing methods for facioscapulohumeral and myotonic muscular dystrophies, and the use of SARM1 inhibitors to block Wallerian degeneration) that will be of significant interest for clinicians and researchers who specialize in neuromuscular disease.
PubMed: 37283936
DOI: 10.17879/freeneuropathology-2023-4682 -
Nature Reviews. Neuroscience Apr 2020Wallerian degeneration is a widespread mechanism of programmed axon degeneration. In the three decades since the discovery of the Wallerian degeneration slow (Wld)... (Review)
Review
Wallerian degeneration is a widespread mechanism of programmed axon degeneration. In the three decades since the discovery of the Wallerian degeneration slow (Wld) mouse, research has generated extensive knowledge of the molecular mechanisms underlying Wallerian degeneration, demonstrated its involvement in non-injury disorders and found multiple ways to block it. Recent developments have included: the detection of NMNAT2 mutations that implicate Wallerian degeneration in rare human diseases; the capacity for lifelong rescue of a lethal condition related to Wallerian degeneration in mice; the discovery of 'druggable' enzymes, including SARM1 and MYCBP2 (also known as PHR1), in Wallerian pathways; and the elucidation of protein structures to drive further understanding of the underlying mechanisms and drug development. Additionally, new data have indicated the potential of these advances to alleviate a number of common disorders, including chemotherapy-induced and diabetic peripheral neuropathies, traumatic brain injury, and amyotrophic lateral sclerosis.
Topics: Animals; Armadillo Domain Proteins; Cytoskeletal Proteins; Disease Models, Animal; Drosophila melanogaster; Humans; Mice; Mice, Transgenic; NAD; Nicotinamide-Nucleotide Adenylyltransferase; Signal Transduction; Translational Research, Biomedical; Wallerian Degeneration
PubMed: 32152523
DOI: 10.1038/s41583-020-0269-3 -
Antioxidants & Redox Signaling Dec 2023The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance. Axonal degeneration is a feature of peripheral neuropathies, glaucoma,... (Review)
Review
The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance. Axonal degeneration is a feature of peripheral neuropathies, glaucoma, and traumatic brain injury, and an early event in neurodegenerative diseases. Since the discovery of Wallerian degeneration (WD), a molecular program that hijacks nicotinamide adenine dinucleotide (NAD) metabolism for axonal self-destruction, the complex roles of NAD in axonal viability and disease have become research priority. The discoveries of the protective Wallerian degeneration slow (Wld) and of sterile alpha and TIR motif containing 1 (SARM1) activation as the main instructive signal for WD have shed new light on the regulatory role of NAD in axonal degeneration in a growing number of neurological diseases. SARM1 has been characterized as a NAD hydrolase and sensor of NAD metabolism. The discovery of regulators of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) proteostasis in axons, the allosteric regulation of SARM1 by NAD and NMN, and the existence of clinically relevant windows of action of these signals has opened new opportunities for therapeutic interventions, including SARM1 inhibitors and modulators of NAD metabolism. Events upstream and downstream of SARM1 remain unclear. Furthermore, manipulating NAD metabolism, an overdetermined process crucial in cell survival, for preventing the degeneration of the injured axon may be difficult and potentially toxic. There is a need for clarification of the distinct roles of NAD metabolism in axonal maintenance as contrasted to WD. There is also a need to better understand the role of NAD metabolism in axonal endangerment in neuropathies, diseases of the white matter, and the early stages of neurodegenerative diseases of the central nervous system. 39, 1167-1184.
Topics: Humans; Wallerian Degeneration; NAD; Peripheral Nervous System Diseases; Axons; Neurodegenerative Diseases
PubMed: 37503611
DOI: 10.1089/ars.2023.0350 -
Current Opinion in Neurobiology Aug 2019Injury-induced axon degeneration in model organisms and cell culture has emerged as an area of growing interest due to its experimental tractability and to the promise... (Review)
Review
Injury-induced axon degeneration in model organisms and cell culture has emerged as an area of growing interest due to its experimental tractability and to the promise of identifying conserved mechanisms that mediate axon loss in human disease. Injury-induced axon degeneration is also observed within the well-studied process of Wallerian degeneration, a complex phenomenon triggered by axon injury to peripheral nerves in mammals. Recent studies have led to the identification of key molecular components of injury-induced axon degeneration. Axon survival factors, such as NMNAT2, act to protect injured axons from degeneration. By contrast, factors such as SARM1, MAPK, and PHR1 act to promote degeneration. The coordinated activity of these factors determines axon fate after injury. Since axon loss is an early feature of neurodegenerative diseases, it is possible that understanding the molecular mechanism of injury-induced degeneration will lead to new treatments for axon loss in neurodegenerative disease. Here, we discuss the critical pathways for injury-induced axon degeneration across species with an emphasis on their interactions in an integrated signaling network.
Topics: Animals; Axons; Humans; Neurodegenerative Diseases; Nicotinamide-Nucleotide Adenylyltransferase; Signal Transduction; Wallerian Degeneration
PubMed: 31071521
DOI: 10.1016/j.conb.2019.03.006 -
Cellular and Molecular Life Sciences :... Feb 2022Injury to the spinal cord is devastating. Studies have implicated Wallerian degeneration as the main cause of axonal destruction in the wake of spinal cord injury.... (Review)
Review
Injury to the spinal cord is devastating. Studies have implicated Wallerian degeneration as the main cause of axonal destruction in the wake of spinal cord injury. Therefore, the suppression of Wallerian degeneration could be beneficial for spinal cord injury treatment. Sterile alpha and armadillo motif-containing protein 1 (SARM1) is a key modulator of Wallerian degeneration, and its impediment can improve spinal cord injury to a significant degree. In this report, we analyze the various signaling domains of SARM1, the recent findings on Wallerian degeneration and its relation to axonal insults, as well as its connection to SARM1, the mitogen-activated protein kinase (MAPK) signaling, and the survival factor, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2). We then elaborate on the possible role of SARM1 in spinal cord injury and explicate how its obstruction could potentially alleviate the injury.
Topics: Armadillo Domain Proteins; Axons; Cytoskeletal Proteins; Humans; Signal Transduction; Spinal Cord Injuries; Wallerian Degeneration
PubMed: 35224705
DOI: 10.1007/s00018-022-04195-4 -
Neuron May 2002alpha-Synucleinopathies are neurodegenerative disorders that range pathologically from the demise of select groups of nuclei to pervasive degeneration throughout the...
alpha-Synucleinopathies are neurodegenerative disorders that range pathologically from the demise of select groups of nuclei to pervasive degeneration throughout the neuraxis. Although mounting evidence suggests that alpha-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human alpha-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, alpha-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal alpha-synuclein inclusions paralleling disease onset, and the alpha-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the alpha-synuclein inclusions contained 10-16 nm wide fibrils similar to human pathological inclusions. These mice demonstrate that A53T alpha-synuclein leads to the formation of toxic filamentous alpha-synuclein neuronal inclusions that cause neurodegeneration.
Topics: Animals; Axons; Behavior, Animal; Brain; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Inclusion Bodies; Male; Mice; Mice, Transgenic; Microscopy, Electron; Movement Disorders; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Phenotype; Recombinant Fusion Proteins; Solubility; Spinal Cord; Synucleins; Wallerian Degeneration; alpha-Synuclein
PubMed: 12062037
DOI: 10.1016/s0896-6273(02)00682-7 -
Journal of Neuroinflammation Oct 2021Plenty of macrophages are recruited to the injured nerve to play key roles in the immunoreaction and engulf the debris of degenerated axons and myelin during Wallerian...
BACKGROUND
Plenty of macrophages are recruited to the injured nerve to play key roles in the immunoreaction and engulf the debris of degenerated axons and myelin during Wallerian degeneration, thus creating a conducive microenvironment for nerve regeneration. Recently, drugs targeting the RhoA pathway have been widely used to promote peripheral axonal regeneration. However, the role of RhoA in macrophage during Wallerian degeneration and nerve regeneration after peripheral nerve injury is still unknown. Herein, we come up with the hypothesis that RhoA might influence Wallerian degeneration and nerve regeneration by affecting the migration and phagocytosis of macrophages after peripheral nerve injury.
METHODS
Immunohistochemistry, Western blotting, H&E staining, and electrophysiology were performed to access the Wallerian degeneration and axonal regeneration after sciatic nerve transection and crush injury in the Lyz; RhoA (cKO) mice or Lyz2 (Cre) mice, regardless of sex. Macrophages' migration and phagocytosis were detected in the injured nerves and the cultured macrophages. Moreover, the expression and potential roles of ROCK and MLCK were also evaluated in the cultured macrophages.
RESULTS
1. RhoA was specifically knocked out in macrophages of the cKO mice; 2. The segmentation of axons and myelin, the axonal regeneration, and nerve conduction in the injured nerve were significantly impeded while the myoatrophy was more severe in the cKO mice compared with those in Cre mice; 3. RhoA knockout attenuated the migration and phagocytosis of macrophages in vivo and in vitro; 4. ROCK and MLCK were downregulated in the cKO macrophages while inhibition of ROCK and MLCK could weaken the migration and phagocytosis of macrophages.
CONCLUSIONS
Our findings suggest that RhoA depletion in macrophages exerts a detrimental effect on Wallerian degeneration and nerve regeneration, which is most likely due to the impaired migration and phagocytosis of macrophages resulted from disrupted RhoA/ROCK/MLCK pathway. Since previous research has proved RhoA inhibition in neurons was favoring for axonal regeneration, the present study reminds us of that the cellular specificity of RhoA-targeted drugs is needed to be considered in the future application for treating peripheral nerve injury.
Topics: Animals; Cell Movement; Cells, Cultured; Female; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peripheral Nerve Injuries; Wallerian Degeneration; rhoA GTP-Binding Protein
PubMed: 34654444
DOI: 10.1186/s12974-021-02292-y -
Annual Review of Neuroscience 2010Traditionally, researchers have believed that axons are highly dependent on their cell bodies for long-term survival. However, recent studies point to the existence of... (Review)
Review
Traditionally, researchers have believed that axons are highly dependent on their cell bodies for long-term survival. However, recent studies point to the existence of axon-autonomous mechanism(s) that regulate rapid axon degeneration after axotomy. Here, we review the cellular and molecular events that underlie this process, termed Wallerian degeneration. We describe the biphasic nature of axon degeneration after axotomy and our current understanding of how Wld(S)--an extraordinary protein formed by fusing a Ube4b sequence to Nmnat1--acts to protect severed axons. Interestingly, the neuroprotective effects of Wld(S) span all species tested, which suggests that there is an ancient, Wld(S)-sensitive axon destruction program. Recent studies with Wld(S) also reveal that Wallerian degeneration is genetically related to several dying back axonopathies, thus arguing that Wallerian degeneration can serve as a useful model to understand, and potentially treat, axon degeneration in diverse traumatic or disease contexts.
Topics: Animals; Axons; Axotomy; Gene Fusion; Humans; Nerve Tissue Proteins; Nicotinamide-Nucleotide Adenylyltransferase; Ubiquitin-Protein Ligases; Wallerian Degeneration
PubMed: 20345246
DOI: 10.1146/annurev-neuro-060909-153248