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Paglione M, Restivo L, Zakhia S, Llobet Rosell A, Terenzio M, Neukomm LJ. Local translatome sustains synaptic function in impaired Wallerian degeneration. EMBO Rep 2025; 26:61-83. [PMID: 39482489 PMCID: PMC11724096 DOI: 10.1038/s44319-024-00301-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 10/07/2024] [Accepted: 10/17/2024] [Indexed: 11/03/2024] Open
Abstract
After injury, severed axons separated from their somas activate programmed axon degeneration, a conserved pathway to initiate their degeneration within a day. Conversely, severed projections deficient in programmed axon degeneration remain morphologically preserved with functional synapses for weeks to months after axotomy. How this synaptic function is sustained remains currently unknown. Here, we show that dNmnat overexpression attenuates programmed axon degeneration in distinct neuronal populations. Severed projections remain morphologically preserved for weeks. When evoked, they elicit a postsynaptic behavior, a readout for preserved synaptic function. We used ribosomal pulldown to isolate the translatome from these projections 1 week after axotomy. Translatome candidates of enriched biological classes identified by transcriptional profiling are validated in a screen using a novel automated system to detect evoked antennal grooming as a proxy for preserved synaptic function. RNAi-mediated knockdown reveals that transcripts of the mTORC1 pathway, a mediator of protein synthesis, and of candidate genes involved in protein ubiquitination and Ca2+ homeostasis are required for preserved synaptic function. Our translatome dataset also uncovers several uncharacterized Drosophila genes associated with human disease. It may offer insights into novel avenues for therapeutic treatments.
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Affiliation(s)
- Maria Paglione
- Department of Fundamental Neurosciences, University of Lausanne, 1005, Lausanne, Switzerland
- Lemanic Neuroscience Doctoral School (LNDS), Lausanne, Switzerland
| | - Leonardo Restivo
- Department of Fundamental Neurosciences, University of Lausanne, 1005, Lausanne, Switzerland
| | - Sarah Zakhia
- Molecular Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Kunigami-gun, Okinawa, 904-0412, Japan
| | - Arnau Llobet Rosell
- Department of Fundamental Neurosciences, University of Lausanne, 1005, Lausanne, Switzerland
| | - Marco Terenzio
- Molecular Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Kunigami-gun, Okinawa, 904-0412, Japan
| | - Lukas J Neukomm
- Department of Fundamental Neurosciences, University of Lausanne, 1005, Lausanne, Switzerland.
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Neuman K, Zhang X, Lejeune BT, Pizzarella D, Vázquez M, Lewis LH, Koppes AN, Koppes RA. Static Magnetic Stimulation and Magnetic Microwires Synergistically Enhance and Guide Neurite Outgrowth. Adv Healthc Mater 2025; 14:e2403956. [PMID: 39568232 PMCID: PMC11773108 DOI: 10.1002/adhm.202403956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Indexed: 11/22/2024]
Abstract
Axonal growth is heavily influenced by topography and biophysical stimuli including magnetic and electrical fields. Despite extensive investigation, the degree of influence and the underlying genetic mechanisms remain poorly understood. Here, a novel approach to guide neurite growth is undertaken using an innovative ferromagnetic composite material - glass-coated magnetic microwire - to furnish a synergistic combination of magnetic and topographical cues. Whole rat dorsal root ganglia (DRG) are cultured under five different conditions: control, static magnetic field, magnetic microwire, static magnetic field + glass fiber, and static magnetic field + magnetic microwire. DRG outgrowth responses under each condition, including total neurite outgrowth and directionality, are compared. The combination of both magnetic stimulation and topography significantly increases total neurite outgrowth compared to the controls. The combination of magnetic stimulation and magnetic microwire lead to a strong directional bias of growth along the microwire, double what is observed with the glass fiber. Next generation RNA sequencing of DRG exposed to static magnetic field + magnetic microwire reveals the downregulation of genes relating to the immune response, interleukin signaling, and signal transduction. These results set the stage for contemplating future biophysical stimulation for axonal guidance and improved understanding of material-tissue interactions.
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Affiliation(s)
- Katelyn Neuman
- Dept. of Chemical EngineeringNortheastern UniversityBostonMA02115USA
| | - Xiaoyu Zhang
- Dept. of Mechanical and Industrial EngineeringNortheastern UniversityBostonMA02115USA
| | - Brian. T. Lejeune
- Dept. of Chemical EngineeringNortheastern UniversityBostonMA02115USA
| | | | - Manuel Vázquez
- Instituto de Ciencia de Materiales de MadridCSICMadrid28049Spain
| | - Laura H. Lewis
- Dept. of Chemical EngineeringNortheastern UniversityBostonMA02115USA
- Dept. of Mechanical and Industrial EngineeringNortheastern UniversityBostonMA02115USA
| | - Abigail N. Koppes
- Dept. of Chemical EngineeringNortheastern UniversityBostonMA02115USA
- Dept. of BioengineeringNortheastern UniversityBostonMA02115USA
- Dept. of BiologyNortheastern UniversityBostonMA02115USA
| | - Ryan A. Koppes
- Dept. of Chemical EngineeringNortheastern UniversityBostonMA02115USA
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Boesch JM, Elmore W, Parry S, Wong S, de Miguel Garcia C, Pearson E, Campoy L, Hon SA. Cryoneurolysis of the saphenous nerve in the pig: A proof-of-principle investigation. Vet Anaesth Analg 2024; 51:677-685. [PMID: 39198104 DOI: 10.1016/j.vaa.2024.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 07/08/2024] [Accepted: 07/08/2024] [Indexed: 09/01/2024]
Abstract
OBJECTIVE To determine if in vivo cryoneurolysis inhibits ex vivo compound action potential (CAP) conduction in the porcine saphenous nerve and if this occurs rapidly enough to justify performing the technique before stifle surgery. STUDY DESIGN Blinded, controlled, randomized, preclinical study. ANIMALS A group of eight healthy, 8 weeks old, intact, female pigs anesthetized for an unrelated terminal study. METHODS Both saphenous nerves of each pig were exposed surgically, and 15 mm of a 20 gauge, closed-tip, commercial cryoneurolysis cannula were inserted cranial to each nerve within the neurovascular fascial sheath along its long axis. The cannula was only actuated on one limb, according to random allocation. Nerves were excised within 15 minutes of actuation and underwent testing in a nerve conduction chamber, where stimulus voltage was increased sequentially (from 0.1 to ≤ 1.9 V). An anesthesiologist blinded to treatment viewed recordings of time versus voltage for each nerve and answered 'yes' or 'no' when asked if an evoked CAP was observed. Fisher's exact test evaluated the incidence of CAP conduction between groups (p < 0.05 considered significant). Nerves were submitted for hematoxylin and eosin staining for blinded histopathological examination. RESULTS A CAP was conducted in 8/8 and 1/8 of the control and treated nerves, respectively (p = 0.001). Maximal responses in control nerves were 1.92 ± 0.19 mV (mean ± standard error). In the single treated nerve that conducted a CAP, the maximal CAP amplitude was 0.4 mV, lower than the lowest maximal CAP (1.19 mV) in the control nerves. All control nerves were histologically normal, and all treated nerves displayed mild perivascular and perineural inflammation (cuffs of lymphocytes, plasma cells and eosinophils, and edema). CONCLUSIONS AND CLINICAL RELEVANCE The rapid inhibition of CAP conduction warrants clinical investigation of saphenous cryoneurolysis for both intraoperative antinociception and postoperative analgesia in pigs undergoing experimental stifle surgery.
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Affiliation(s)
- Jordyn M Boesch
- Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA.
| | - Wilhelm Elmore
- Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Stephen Parry
- Statistical Consulting Unit, Cornell University, Ithaca, NY, USA
| | - Shanna Wong
- Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | | | - Emily Pearson
- Center for Animal Resources and Education (CARE), Cornell University, Ithaca, NY, USA
| | - Luis Campoy
- Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Stephanie A Hon
- Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
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Blank N, Weiner M, Patel S, Köhler S, Thaiss CA. Mind the GAPS: Glia associated with psychological stress. J Neuroendocrinol 2024:e13451. [PMID: 39384366 DOI: 10.1111/jne.13451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 09/01/2024] [Accepted: 09/05/2024] [Indexed: 10/11/2024]
Abstract
Glial cells are an integral component of the nervous system, performing crucial functions that extend beyond structural support, including modulation of the immune system, tissue repair, and maintaining tissue homeostasis. Recent studies have highlighted the importance of glial cells as key mediators of stress responses across different organs. This review focuses on the roles of glial cells in peripheral tissues in health and their involvement in diseases linked to psychological stress. Populations of glia associated with psychological stress ("GAPS") emerge as a promising target cell population in our basic understanding of stress-associated pathologies, highlighting their role as mediators of the deleterious effects of psychological stress on various health conditions. Ultimately, new insights into the impact of stress on glial cell populations in the periphery may support clinical efforts aimed at improving the psychological state of patients for improved health outcomes.
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Affiliation(s)
- Niklas Blank
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Molly Weiner
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Shaan Patel
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sarah Köhler
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Christoph A Thaiss
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Kaszás D, Enyedi B. Addressing burning questions on axon regeneration. eLife 2024; 13:e101093. [PMID: 39172507 PMCID: PMC11341088 DOI: 10.7554/elife.101093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024] Open
Abstract
Regeneration of sensory axons after a burn injury depends on early keratinocyte responses regulated by the wound microenvironment.
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Affiliation(s)
- Diána Kaszás
- Department of Physiology, Faculty of Medicine, Semmelweis UniversityBudapestHungary
| | - Balázs Enyedi
- Department of Physiology, Faculty of Medicine, Semmelweis UniversityBudapestHungary
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Delibaş B, Kaplan AA, Marangoz AH, Eltahir MI, Altun G, Kaplan S. The effect of dietary sesame oil and ginger oil as antioxidants in the adult rat dorsal root ganglia after peripheral nerve crush injury. Int J Neurosci 2024; 134:714-724. [PMID: 36342428 DOI: 10.1080/00207454.2022.2145475] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 11/04/2022] [Indexed: 11/09/2022]
Abstract
AIM The purpose of this study was to investigate the effect of dietary sesame oil and ginger oil supplements on the dorsal root ganglia following a sciatic nerve crush model in male Wistar albino rats. MATERIALS AND METHODS Crush injury models have been done by means of graded forceps (50 Newton). The animals were given a daily sesame oil (4 ml/kg/day) and ginger oil (400 mg/kg/day) via oral gavage for a period of 28 days. Dorsal root ganglia from the L5 levels were harvested. Processing of tissues was done for electron microscopy and light microscopy. Immunohistochemical staining with active caspase-3 antibody and qualitative ultrastructural analyses of tissues were made by a light and a transmission electron microscope, respectively. RESULTS The results showed that crush injury leads to remarkable ultrastructural changes in sensory neurons, such as swollen mitochondria, disruption of cristae structure, glial cell proliferation and, consequently, phagocytosis of the damaged neuron. These ultrastructural changes were less evident in the treated groups, and both natural compounds reduced the expression of activated caspase-3, which may also affect ultrastructural changes. CONCLUSION The application of the natural products sesame oil and ginger oil may represent a supportive approach to the protection of sensory neurons against the destructive effects of peripheral nerve crush injury.
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Affiliation(s)
- Burcu Delibaş
- Departments of Histology and Embryology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
| | - Arife Ahsen Kaplan
- Department of Histology and Embryology, Faculty of Medicine, İstanbul Medipol University, İstanbul, Turkey
| | | | - Mohammed Issa Eltahir
- Departments of Histology and Embryology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
- Faculty of Medicine, National University, Khartoum, Sudan
| | - Gamze Altun
- Departments of Histology and Embryology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
| | - Suleyman Kaplan
- Departments of Histology and Embryology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
- Nelson Mandela African Institute of Science and Technology, Arusha, Tanzania
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Stassart RM, Gomez-Sanchez JA, Lloyd AC. Schwann Cells as Orchestrators of Nerve Repair: Implications for Tissue Regeneration and Pathologies. Cold Spring Harb Perspect Biol 2024; 16:a041363. [PMID: 38199866 PMCID: PMC11146315 DOI: 10.1101/cshperspect.a041363] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2024]
Abstract
Peripheral nerves exist in a stable state in adulthood providing a rapid bidirectional signaling system to control tissue structure and function. However, following injury, peripheral nerves can regenerate much more effectively than those of the central nervous system (CNS). This multicellular process is coordinated by peripheral glia, in particular Schwann cells, which have multiple roles in stimulating and nurturing the regrowth of damaged axons back to their targets. Aside from the repair of damaged nerves themselves, nerve regenerative processes have been linked to the repair of other tissues and de novo innervation appears important in establishing an environment conducive for the development and spread of tumors. In contrast, defects in these processes are linked to neuropathies, aging, and pain. In this review, we focus on the role of peripheral glia, especially Schwann cells, in multiple aspects of nerve regeneration and discuss how these findings may be relevant for pathologies associated with these processes.
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Affiliation(s)
- Ruth M Stassart
- Paul-Flechsig-Institute of Neuropathology, University Clinic Leipzig, Leipzig 04103, Germany
| | - Jose A Gomez-Sanchez
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante 03010, Spain
- Instituto de Neurociencias CSIC-UMH, Sant Joan de Alicante 03550, Spain
| | - Alison C Lloyd
- UCL Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, United Kingdom
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Irisarri C. History of peripheral nerve injuries. J Hand Surg Eur Vol 2024; 49:812-823. [PMID: 37728740 DOI: 10.1177/17531934231198455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/21/2023]
Abstract
This article reviews the history of peripheral nerve (PN) injuries and successive advances in their management by notable pioneers, an interesting topic that I chose for my Doctoral Thesis in 1990 in Madrid. Mentioning all their names and contributions is an obligatory tribute, and I offer my sincere apologies for inevitably leaving a few out. For half a century I have witnessed microsurgery advances, and also experienced frequent failures in my practice with the use of new techniques; a testimony that we are very far from achieving the 'Holy Grail' of complete PN recovery for these injuries. Our experience is often like a pendulum, from nihilism to optimism and vice versa. Many factors influence the results of PN repair. Fortunately, microsurgery has been a breakthrough but, too often, emergency surgery is carried out by surgeons without enough tools and experience, both very important factors in this field.
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Garb J, Amitai G, Lu A, Ofir G, Brandis A, Mehlman T, Kranzusch PJ, Sorek R. The SARM1 TIR domain produces glycocyclic ADPR molecules as minor products. PLoS One 2024; 19:e0302251. [PMID: 38635746 PMCID: PMC11025887 DOI: 10.1371/journal.pone.0302251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 03/31/2024] [Indexed: 04/20/2024] Open
Abstract
Sterile alpha and TIR motif-containing 1 (SARM1) is a protein involved in programmed death of injured axons. Following axon injury or a drug-induced insult, the TIR domain of SARM1 degrades the essential molecule nicotinamide adenine dinucleotide (NAD+), leading to a form of axonal death called Wallerian degeneration. Degradation of NAD+ by SARM1 is essential for the Wallerian degeneration process, but accumulating evidence suggest that other activities of SARM1, beyond the mere degradation of NAD+, may be necessary for programmed axonal death. In this study we show that the TIR domains of both human and fruit fly SARM1 produce 1''-2' and 1''-3' glycocyclic ADP-ribose (gcADPR) molecules as minor products. As previously reported, we observed that SARM1 TIR domains mostly convert NAD+ to ADPR (for human SARM1) or cADPR (in the case of SARM1 from Drosophila melanogaster). However, we now show that human and Drosophila SARM1 additionally convert ~0.1-0.5% of NAD+ into gcADPR molecules. We find that SARM1 TIR domains produce gcADPR molecules both when purified in vitro and when expressed in bacterial cells. Given that gcADPR is a second messenger involved in programmed cell death in bacteria and likely in plants, we propose that gcADPR may play a role in SARM1-induced programmed axonal death in animals.
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Affiliation(s)
- Jeremy Garb
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Gil Amitai
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Allen Lu
- Department of Microbiology, Harvard Medical School, Boston, MA, United States of America
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, United States of America
| | - Gal Ofir
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Alexander Brandis
- Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Tevie Mehlman
- Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Philip J Kranzusch
- Department of Microbiology, Harvard Medical School, Boston, MA, United States of America
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, United States of America
- Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA, United States of America
| | - Rotem Sorek
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
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Misra S, Takagi T, Yamaguchi S, Anami Y, Takayama S. Intercostal nerve transfer in management of biceps and triceps co-contraction in brachial plexus birth palsy. Microsurgery 2024; 44:e31155. [PMID: 38376257 DOI: 10.1002/micr.31155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 12/18/2023] [Accepted: 02/01/2024] [Indexed: 02/21/2024]
Abstract
OBJECTIVE Brachial plexus birth palsy (BPBP) is often caused by traction during birth. In some cases, reinnervation occurs during spontaneous recovery and it causes involuntary co-contraction between antagonistic muscles. When it comes up between the biceps and triceps muscles, smooth active motion of the elbow joint is impaired. We are presenting outcomes of intercostal nerve (ICN) to radial nerve transfer to minimize elbow motion abnormality due to co-contraction. METHODS We present five cases (two males and three females) of biceps and triceps co-contraction in BPBP patients treated from 2005 to 2018. The mean age at surgery was 9.36 years (range, 4.8-16.4 years). They were treated by ICNs transfer to motor branch of the radial nerve to the triceps muscle. Preoperative electromyography was done in all cases to confirm biceps and triceps co-contraction and to assess the contractile status of both muscles. A 10-s flexion extension test was done pre and postoperatively to assess the efficacy of our procedure. RESULTS The postop course was uneventful. No donor site morbidity or respiratory complications were recorded in any patient. The mean postoperative follow-up period was 83.9 months (range, 53.6-135.5 months). At the final follow-up, elbow flexion was M4 in the Medical Research Council (MRC) grading scale in all five patients and elbow extension was graded M4 or M4- in all five patients. There was significant increase in the 10 s flexion extension test results delineating the effectiveness of the procedure. CONCLUSIONS ICNs transfer to motor branch of the radial nerve to the triceps muscle for management of biceps and triceps co-contraction in BPBP is a good option with minimal morbidity and good success rate.
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Affiliation(s)
- Sayantani Misra
- Division of Orthopedic Surgery, Department of Surgical Specialties, National Center for Child Health and Development, Tokyo, Japan
| | - Takehiko Takagi
- Division of Orthopedic Surgery, Department of Surgical Specialties, National Center for Child Health and Development, Tokyo, Japan
| | - Sakura Yamaguchi
- Division of Orthopedic Surgery, Department of Surgical Specialties, National Center for Child Health and Development, Tokyo, Japan
| | - Yoko Anami
- Division of Orthopedic Surgery, Department of Surgical Specialties, National Center for Child Health and Development, Tokyo, Japan
| | - Shinichiro Takayama
- Division of Orthopedic Surgery, Department of Surgical Specialties, National Center for Child Health and Development, Tokyo, Japan
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Limke A, Poschmann G, Stühler K, Petzsch P, Wachtmeister T, von Mikecz A. Silica Nanoparticles Disclose a Detailed Neurodegeneration Profile throughout the Life Span of a Model Organism. J Xenobiot 2024; 14:135-153. [PMID: 38249105 PMCID: PMC10801581 DOI: 10.3390/jox14010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/08/2024] [Accepted: 01/10/2024] [Indexed: 01/23/2024] Open
Abstract
The incidence of age-related neurodegenerative diseases is rising globally. However, the temporal sequence of neurodegeneration throughout adult life is poorly understood. To identify the starting points and schedule of neurodegenerative events, serotonergic and dopaminergic neurons were monitored in the model organism C. elegans, which has a life span of 2-3 weeks. Neural morphology was examined from young to old nematodes that were exposed to silica nanoparticles. Young nematodes showed phenotypes such as dendritic beading of serotonergic and dopaminergic neurons that are normally not seen until late life. During aging, neurodegeneration spreads from specifically susceptible ADF and PDE neurons in young C. elegans to other more resilient neurons, such as dopaminergic CEP in middle-aged worms. Investigation of neurodegenerative hallmarks and animal behavior revealed a temporal correlation with the acceleration of neuromuscular defects, such as internal hatch in 2-day-old C. elegans. Transcriptomics and proteomics of young worms exposed to nano silica showed a change in gene expression concerning the gene ontology groups serotonergic and dopaminergic signaling as well as neuropeptide signaling. Consistent with this, reporter strains for nlp-3, nlp-14 and nlp-21 confirmed premature degeneration of the serotonergic neuron HSN and other neurons in young C. elegans. The results identify young nematodes as a vulnerable age group for nano silica-induced neural defects with a significantly reduced health span. Neurodegeneration of specific neurons impairs signaling by classical neurotransmitters as well as neuropeptides and compromises related neuromuscular behaviors in critical phases of life, such as the reproductive phase.
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Affiliation(s)
- Annette Limke
- IUF–Leibniz Research Institute of Environmental Medicine GmbH, Auf’m Hennekamp 50, 40225 Düsseldorf, Germany
| | - Gereon Poschmann
- Institute of Molecular Medicine, Proteome Research, Medical Faculty and University Hospital, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Kai Stühler
- Molecular Proteomics Laboratory, BMFZ, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Patrick Petzsch
- Biological and Medical Research Center (BMFZ), Medical Faculty, Heinrich-Heine-University, Universitätsstraße 1, 40225 Düsseldorf, Germany
| | - Thorsten Wachtmeister
- Biological and Medical Research Center (BMFZ), Medical Faculty, Heinrich-Heine-University, Universitätsstraße 1, 40225 Düsseldorf, Germany
| | - Anna von Mikecz
- IUF–Leibniz Research Institute of Environmental Medicine GmbH, Auf’m Hennekamp 50, 40225 Düsseldorf, Germany
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Gerasimov AA, Burmatov NA, Kopylov SA. [Peripheral nerves' function recovery by intratissual electric stimulation]. VOPROSY KURORTOLOGII, FIZIOTERAPII, I LECHEBNOI FIZICHESKOI KULTURY 2024; 102:36-44. [PMID: 39248585 DOI: 10.17116/kurort202410104136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/10/2024]
Abstract
An intratissual electrical stimulation, accompanied by irritation of their central neurons, is used to recover the function of damaged peripheral nerves. Treatment results exceeded those with the use of cutaneous electrical stimulation, which is confirmed by comparative results of trial animal experiments. The time and quality of peripheral nerves' function recovery in comparison of intratissual and cutaneous electrical stimulation methods remain unknown. OBJECTIVE To evaluate the time and quality of peripheral nerves' functions recovery after their suturing and conducting two different methods of electrical stimulation, namely intratissual and cutaneous, in projection of central neurons of damaged spinal nerves in the postoperative period. MATERIAL AND METHODS The basic technical parameters of the method of peripheral nerves' functions recovery in the postoperative period were ptacticed. Postoperative rehabilitation treatment was performed in 77 patients with traumatic peripheral nerves' injuries at the level of the forearm: in 42 with intratissual electrical stimulation, in 35 - using cutaneous one with similar characteristics of electrical current and concomitant pharmacological therapy. The follow-up duration was 2 years. RESULTS A significant (in 4-6 times) reduction in time of treatment and a greater improvement in qualitative indicators when using intratissual electrical stimulation compared to the use of cutaneous stimulation were obtained. The effectiveness of the restorative therapy was dependent on the number of procedures, and a complete recovery of the damaged peripheral nerves' functions was observed after three courses of intratissual electrical stimulation. CONCLUSION The time and degree of recovery of peripheral nerves' functions depends on the functional activity of their central neurons at the level of the spinal cord. The activation of these neurons by low-frequency electrical current allows to activate their trophic function. Thus, the cutaneous electrical stimulation does not cause the necessary level of irritation of the neurons due to the fact that the skin is a barrier to electrical current, which reduces its impact in 200-500 times. The intratissual electrical stimulation allows to solve the problem by supplying the needle-electrode much closer to the «target». The proposed method of intratissual electrical stimulation has shown its advantage over cutaneous electrical stimulation, significantly reducing the duration of the restorative treatment and increasing its qualitative indicators.
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Loreto A, Antoniou C, Merlini E, Gilley J, Coleman MP. NMN: The NAD precursor at the intersection between axon degeneration and anti-ageing therapies. Neurosci Res 2023; 197:18-24. [PMID: 36657725 DOI: 10.1016/j.neures.2023.01.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/18/2023]
Abstract
The past 20 years of research on axon degeneration has revealed fine details on how NAD biology controls axonal survival. Extensive data demonstrate that the NAD precursor NMN binds to and activates the pro-degenerative enzyme SARM1, so a failure to convert sufficient NMN into NAD leads to toxic NMN accumulation and axon degeneration. This involvement of NMN brings the axon degeneration field to an unexpected overlap with research into ageing and extending healthy lifespan. A decline in NAD levels throughout life, at least in some tissues, is believed to contribute to age-related functional decay and boosting NAD production with supplementation of NMN or other NAD precursors has gained attention as a potential anti-ageing therapy. Recent years have witnessed an influx of NMN-based products and related molecules on the market, sold as food supplements, with many people taking these supplements daily. While several clinical trials are ongoing to check the safety profiles and efficacy of NAD precursors, sufficient data to back their therapeutic use are still lacking. Here, we discuss NMN supplementation, SARM1 and anti-ageing strategies, with an important question in mind: considering that NMN accumulation can lead to axon degeneration, how is this compatible with its beneficial effect in ageing and are there circumstances in which NMN supplementation could become harmful?
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Affiliation(s)
- Andrea Loreto
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK.
| | - Christina Antoniou
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK
| | - Elisa Merlini
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK
| | - Jonathan Gilley
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK
| | - Michael P Coleman
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK.
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Otsuki M, Terenzio M. Mechanisms of axonal degeneration and regeneration of the nervous system. Neurosci Res 2023; 197:1-2. [PMID: 37839523 DOI: 10.1016/j.neures.2023.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2023]
Affiliation(s)
- Miki Otsuki
- Molecular Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Kunigami-gun, Okinawa 904-0412, Japan
| | - Marco Terenzio
- Molecular Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Kunigami-gun, Okinawa 904-0412, Japan.
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Alexandris AS, Koliatsos VE. NAD +, Axonal Maintenance, and Neurological Disease. Antioxid Redox Signal 2023; 39:1167-1184. [PMID: 37503611 PMCID: PMC10715442 DOI: 10.1089/ars.2023.0350] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 05/28/2023] [Indexed: 07/29/2023]
Abstract
Significance: 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. Recent Advances: The discoveries of the protective Wallerian degeneration slow (WldS) 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. Critical Issues: 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. Future Directions: 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. Antioxid. Redox Signal. 39, 1167-1184.
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Affiliation(s)
| | - Vassilis E. Koliatsos
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Neurology, and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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16
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Waller TJ, Collins CA. Opposing roles of Fos, Raw, and SARM1 in the regulation of axonal degeneration and synaptic structure. Front Cell Neurosci 2023; 17:1283995. [PMID: 38099151 PMCID: PMC10719852 DOI: 10.3389/fncel.2023.1283995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 10/30/2023] [Indexed: 12/17/2023] Open
Abstract
Introduction The degeneration of injured axons is driven by conserved molecules, including the sterile armadillo TIR domain-containing protein SARM1, the cJun N-terminal kinase JNK, and regulators of these proteins. These molecules are also implicated in the regulation of synapse development though the mechanistic relationship of their functions in degeneration vs. development is poorly understood. Results and discussion Here, we uncover disparate functional relationships between SARM1 and the transmembrane protein Raw in the regulation of Wallerian degeneration and synaptic growth in motoneurons of Drosophila melanogaster. Our genetic data suggest that Raw antagonizes the downstream output MAP kinase signaling mediated by Drosophila SARM1 (dSarm). This relationship is revealed by dramatic synaptic overgrowth phenotypes at the larval neuromuscular junction when motoneurons are depleted for Raw or overexpress dSarm. While Raw antagonizes the downstream output of dSarm to regulate synaptic growth, it shows an opposite functional relationship with dSarm for axonal degeneration. Loss of Raw leads to decreased levels of dSarm in axons and delayed axonal degeneration that is rescued by overexpression of dSarm, supporting a model that Raw promotes the activation of dSarm in axons. However, inhibiting Fos also decreases dSarm levels in axons but has the opposite outcome of enabling Wallerian degeneration. The combined genetic data suggest that Raw, dSarm, and Fos influence each other's functions through multiple points of regulation to control the structure of synaptic terminals and the resilience of axons to degeneration.
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Affiliation(s)
- Thomas J. Waller
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, United States
| | - Catherine A. Collins
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, United States
- Department of Neurosciences, Case Western Reserve University, Cleveland, OH, United States
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von Mikecz A. Elegant Nematodes Improve Our Understanding of Human Neuronal Diseases, the Role of Pollutants and Strategies of Resilience. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023; 57:16755-16763. [PMID: 37874738 PMCID: PMC10634345 DOI: 10.1021/acs.est.3c04580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 10/05/2023] [Accepted: 10/06/2023] [Indexed: 10/26/2023]
Abstract
The prevalence of neurodegenerative disorders such as Alzheimer's and Parkinson's disease are rising globally. The role of environmental pollution in neurodegeneration is largely unknown. Thus, this perspective advocates exposome research in C. elegans models of human diseases. The models express amyloid proteins such as Aβ, recapitulate the degeneration of specifically vulnerable neurons and allow for correlated neurobehavioral phenotyping throughout the entire life span of the nematode. Neurobehavioral traits like locomotion gaits, rigidity, or cognitive decline are quantifiable and carefully mimic key aspects of the human diseases. Underlying molecular pathways of neurodegeneration are elucidated in pollutant-exposed C. elegans Alzheimer's or Parkinson's models by transcriptomics (RNA-seq), mass spectrometry-based proteomics and omics addressing other biochemical traits. Validation of the identified disease pathways can be achieved by genome-wide association studies in matching human cohorts. A consistent One Health approach includes isolation of nematodes from contaminated sites and their comparative investigation by imaging, neurobehavioral profiling and single worm proteomics. C. elegans models of neurodegenerative diseases are likewise well-suited for high throughput methods that provide a promising strategy to identify resilience pathways of neurosafety and keep up with the number of pollutants, nonchemical exposome factors, and their interactions.
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Affiliation(s)
- Anna von Mikecz
- IUF − Leibniz Research Institute
of Environmental Medicine GmbH, Auf’m Hennekamp 50, 40225 Duesseldorf, Germany
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18
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Gitik M, Elberg G, Reichert F, Tal M, Rotshenker S. Deletion of CD47 from Schwann cells and macrophages hastens myelin disruption/dismantling and scavenging in Schwann cells and augments myelin debris phagocytosis in macrophages. J Neuroinflammation 2023; 20:243. [PMID: 37872624 PMCID: PMC10594853 DOI: 10.1186/s12974-023-02929-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 10/10/2023] [Indexed: 10/25/2023] Open
Abstract
BACKGROUND Myelin that surrounds axons breaks in trauma and disease; e.g., peripheral nerve and spinal cord injuries (PNI and SCI) and multiple sclerosis (MS). Resulting myelin debris hinders repair if not effectively scavenged by Schwann cells and macrophages in PNI and by microglia in SCI and MS. We showed previously that myelin debris evades phagocytosis as CD47 on myelin ligates SIRPα (signal regulatory protein-α) on macrophages and microglia, triggering SIRPα to inhibit phagocytosis in phagocytes. Using PNI as a model, we tested the in vivo significance of SIRPα-dependent phagocytosis inhibition in SIRPα null mice, showing that SIRPα deletion leads to accelerated myelin debris clearance, axon regeneration and recovery of function from PNI. Herein, we tested how deletion of CD47, a SIRPα ligand and a cell surface receptor on Schwann cells and phagocytes, affects recovery from PNI. METHODS Using CD47 null (CD47-/-) and wild type mice, we studied myelin disruption/dismantling and debris clearance, axon regeneration and recovery of function from PNI. RESULTS As expected from CD47 on myelin acting as a SIRPα ligand that normally triggers SIRPα-dependent phagocytosis inhibition in phagocytes, myelin debris clearance, axon regeneration and function recovery were all faster in CD47-/- mice than in wild type mice. Unexpectedly compared with wild type mice, myelin debris clearance started sooner and CD47-deleted Schwann cells displayed enhanced disruption/dismantling and scavenging of myelin in CD47-/- mice. Furthermore, CD47-deleted macrophages from CD47-/- mice phagocytosed more myelin debris than CD47-expressing phagocytes from wild type mice. CONCLUSIONS This study reveals two novel normally occurring CD47-dependent mechanisms that impede myelin debris clearance. First, CD47 expressed on Schwann cells inhibits myelin disruption/dismantling and debris scavenging in Schwann cells. Second, CD47 expressed on macrophages inhibits myelin debris phagocytosis in phagocytes. The two add to a third mechanism that we previously documented whereby CD47 on myelin ligates SIRPα on macrophages and microglia, triggering SIRPα-dependent phagocytosis inhibition in phagocytes. Thus, CD47 plays multiple inhibitory roles that combined impede myelin debris clearance, leading to delayed recovery from PNI. Similar inhibitory roles in microglia may hinder recovery from other pathologies in which repair depends on efficient phagocytosis (e.g., SCI and MS).
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Affiliation(s)
- Miri Gitik
- Medical Neurobiology, Faculty of Medicine, IMRIC, Hebrew University, Ein-Kerem Campus, 12272, 91120, Jerusalem, Israel
- Genomic Research Branch, Division of Neuroscience and Basic Behavioral Science (DNBBS), National Institute of Mental Health (NIMH), NIH, Rockville, USA
| | - Gerard Elberg
- Medical Neurobiology, Faculty of Medicine, IMRIC, Hebrew University, Ein-Kerem Campus, 12272, 91120, Jerusalem, Israel
| | - Fanny Reichert
- Medical Neurobiology, Faculty of Medicine, IMRIC, Hebrew University, Ein-Kerem Campus, 12272, 91120, Jerusalem, Israel
| | - Michael Tal
- Medical Neurobiology, Faculties of Medicine and Dentistry, Center for Research on Pain, Hebrew University, Jerusalem, Israel
| | - Shlomo Rotshenker
- Medical Neurobiology, Faculty of Medicine, IMRIC, Hebrew University, Ein-Kerem Campus, 12272, 91120, Jerusalem, Israel.
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Khaled MM, Ibrahium AM, Abdelgalil AI, El-Saied MA, El-Bably SH. Regenerative Strategies in Treatment of Peripheral Nerve Injuries in Different Animal Models. Tissue Eng Regen Med 2023; 20:839-877. [PMID: 37572269 PMCID: PMC10519924 DOI: 10.1007/s13770-023-00559-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/15/2023] [Accepted: 05/21/2023] [Indexed: 08/14/2023] Open
Abstract
BACKGROUND Peripheral nerve damage mainly resulted from traumatic or infectious causes; the main signs of a damaged nerve are the loss of sensory and/or motor functions. The injured nerve has limited regenerative capacity and is recovered by the body itself, the recovery process depends on the severity of damage to the nerve, nowadays the use of stem cells is one of the new and advanced methods for treatment of these problems. METHOD Following our review, data are collected from different databases "Google scholar, Springer, Elsevier, Egyptian Knowledge Bank, and PubMed" using different keywords such as Peripheral nerve damage, Radial Nerve, Sciatic Nerve, Animals, Nerve regeneration, and Stem cell to investigate the different methods taken in consideration for regeneration of PNI. RESULT This review contains tables illustrating all forms and types of regenerative medicine used in treatment of peripheral nerve injuries (PNI) including different types of stem cells " adipose-derived stem cells, bone marrow stem cells, Human umbilical cord stem cells, embryonic stem cells" and their effect on re-constitution and functional recovery of the damaged nerve which evaluated by physical, histological, Immuno-histochemical, biochemical evaluation, and the review illuminated the best regenerative strategies help in rapid peripheral nerve regeneration in different animal models included horse, dog, cat, sheep, monkey, pig, mice and rat. CONCLUSION Old surgical attempts such as neurorrhaphy, autogenic nerve transplantation, and Schwann cell implantation have a limited power of recovery in cases of large nerve defects. Stem cell therapy including mesenchymal stromal cells has a high potential differentiation capacity to renew and form a new nerve and also restore its function.
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Affiliation(s)
- Mona M Khaled
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Cairo University, Giza Square, Giza, 12211, Egypt.
| | - Asmaa M Ibrahium
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Cairo University, Giza Square, Giza, 12211, Egypt
| | - Ahmed I Abdelgalil
- Department of Surgery, Anaesthesiology and Radiology, Faculty of Veterinary Medicine, Cairo University, Giza Square, Giza, 12211, Egypt
| | - Mohamed A El-Saied
- Department of Pathology, Faculty of Veterinary of Veterinary Medicine, Cairo University, Giza Square, Giza, 12211, Egypt
| | - Samah H El-Bably
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Cairo University, Giza Square, Giza, 12211, Egypt
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Hansson MJ, Elmér E. Cyclosporine as Therapy for Traumatic Brain Injury. Neurotherapeutics 2023; 20:1482-1495. [PMID: 37561274 PMCID: PMC10684836 DOI: 10.1007/s13311-023-01414-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2023] [Indexed: 08/11/2023] Open
Abstract
Drug development in traumatic brain injury (TBI) has been impeded by the complexity and heterogeneity of the disease pathology, as well as limited understanding of the secondary injury cascade that follows the initial trauma. As a result, patients with TBI have an unmet need for effective pharmacological therapies. One promising drug candidate is cyclosporine, a polypeptide traditionally used to achieve immunosuppression in transplant recipients. Cyclosporine inhibits mitochondrial permeability transition, thereby reducing secondary brain injury, and has shown neuroprotective effects in multiple preclinical models of TBI. Moreover, the cyclosporine formulation NeuroSTAT® displayed positive effects on injury biomarker levels in patients with severe TBI enrolled in the Phase Ib/IIa Copenhagen Head Injury Ciclosporin trial (NCT01825044). Future research on neuroprotective compounds such as cyclosporine should take advantage of recent advances in fluid-based biomarkers and neuroimaging to select patients with similar disease pathologies for clinical trials. This would increase statistical power and allow for more accurate assessment of long-term outcomes.
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Affiliation(s)
- Magnus J Hansson
- Abliva AB, Lund, Sweden.
- Department of Clinical Sciences, Mitochondrial Medicine, Lund University, Lund, Sweden.
| | - Eskil Elmér
- Abliva AB, Lund, Sweden
- Department of Clinical Sciences, Mitochondrial Medicine, Lund University, Lund, Sweden
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21
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Nij Bijvank J, Maillette de Buy Wenniger L, de Graaf P, Petzold A. Clinical review of retinotopy. Br J Ophthalmol 2023; 107:304-312. [PMID: 34887243 DOI: 10.1136/bjophthalmol-2021-320563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 11/14/2021] [Indexed: 11/03/2022]
Abstract
Two observations made 29 years apart are the cornerstones of this review on the contributions of Dr Gordon T. Plant to understanding pathology affecting the optic nerve. The first observation laid the anatomical basis in 1990 for the interpretation of optical coherence tomography (OCT) findings in 2009. Retinal OCT offers clinicians detailed in vivo structural imaging of individual retinal layers. This has led to novel observations which were impossible to make using ophthalmoscopy. The technique also helps to re-introduce the anatomically grounded concept of retinotopy to clinical practise. This review employs illustrations of the anatomical basis for retinotopy through detailed translational histological studies and multimodal brain-eye imaging studies. The paths of the prelaminar and postlaminar axons forming the optic nerve and their postsynaptic path from the dorsal lateral geniculate nucleus to the primary visual cortex in humans are described. With the mapped neuroanatomy in mind we use OCT-MRI pairings to discuss the patterns of neurodegeneration in eye and brain that are a consequence of the hard wired retinotopy: anterograde and retrograde axonal degeneration which can, within the visual system, propagate trans-synaptically. The technical advances of OCT and MRI for the first time enable us to trace axonal degeneration through the entire visual system at spectacular resolution. In conclusion, the neuroanatomical insights provided by the combination of OCT and MRI allows us to separate incidental findings from sinister pathology and provides new opportunities to tailor and monitor novel neuroprotective strategies.
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Affiliation(s)
- Jenny Nij Bijvank
- Departments of Ophthalmology and Neurology, Expertise Centre Neuro-ophthalmology, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
| | | | - Pim de Graaf
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.,Department of Neurology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Axel Petzold
- Departments of Ophthalmology and Neurology, Expertise Centre Neuro-ophthalmology, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands .,Moorfields Eye Hospital, City Road; The National Hospital for Neurology and Neurosurgery and the UCL Institute of Neurology, Queen Square, London, London, UK
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22
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Goyal V, Read AT, Brown DM, Brawer L, Bateh K, Hannon BG, Feola AJ, Ethier CR. Morphometric Analysis of Retinal Ganglion Cell Axons in Normal and Glaucomatous Brown Norway Rats Optic Nerves. Transl Vis Sci Technol 2023; 12:8. [PMID: 36917118 PMCID: PMC10020949 DOI: 10.1167/tvst.12.3.8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 11/23/2022] [Indexed: 03/15/2023] Open
Abstract
Purpose A reference atlas of optic nerve (ON) retinal ganglion cell (RGC) axons could facilitate studies of neuro-ophthalmic diseases by detecting subtle RGC axonal changes. Here we construct an RGC axonal atlas for normotensive eyes in Brown Norway rats, widely used in glaucoma research, and also develop/evaluate several novel metrics of axonal damage in hypertensive eyes. Methods Light micrographs of entire ON cross-sections from hypertensive and normotensive eyes were processed through a deep learning-based algorithm, AxoNet2.0, to determine axonal morphological properties and were semiquantitatively scored using the Morrison grading scale (MGS) to provide a damage score independent of AxoNet2.0 outcomes. To construct atlases, ONs were conformally mapped onto an ON "template," and axonal morphometric data was computed for each region. We also developed damage metrics based on myelin morphometry. Results In normotensive eyes, average axon density was ∼0.3 axons/µm2 (i.e., ∼80,000 axons in an ON). We measured axoplasm diameter, eccentricity, cross-sectional area, and myelin g-ratio and thickness. Most morphological parameters exhibited a wide range of coefficients of variation (CoV); however, myelin thickness CoV was only ∼2% in normotensive eyes. In hypertensive eyes, increased myelin thickness correlated strongly with MGS (P < 0.0001). Conclusions We present the first comprehensive normative RGC axon morphometric atlas for Brown Norway rat eyes. We suggest objective, repeatable damage metrics based on RGC axon myelin thickness for hypertensive eyes. Translational Relevance These tools can evaluate regional changes in RGCs and overall levels of damage in glaucoma studies using Brown Norway rats.
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Affiliation(s)
- Vidisha Goyal
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - A. Thomas Read
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Dillon M. Brown
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Luke Brawer
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Kaitlyn Bateh
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Bailey G. Hannon
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Andrew J. Feola
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA
- Department of Ophthalmology, Emory University, Atlanta, GA, USA
| | - C. Ross Ethier
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
- Department of Ophthalmology, Emory University, Atlanta, GA, USA
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23
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Lopes G, Nogueira J, Dimitriadis G, Menendez JA, Paton JJ, Kampff AR. A robust role for motor cortex. Front Neurosci 2023; 17:971980. [PMID: 36845435 PMCID: PMC9950416 DOI: 10.3389/fnins.2023.971980] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 01/11/2023] [Indexed: 02/12/2023] Open
Abstract
The role of motor cortex in non-primate mammals remains unclear. More than a century of stimulation, anatomical and electrophysiological studies has implicated neural activity in this region with all kinds of movement. However, following the removal of motor cortex, rats retain most of their adaptive behaviors, including previously learned skilled movements. Here we revisit these two conflicting views of motor cortex and present a new behavior assay, challenging animals to respond to unexpected situations while navigating a dynamic obstacle course. Surprisingly, rats with motor cortical lesions show clear impairments facing an unexpected collapse of the obstacles, while showing no impairment with repeated trials in many motor and cognitive metrics of performance. We propose a new role for motor cortex: extending the robustness of sub-cortical movement systems, specifically to unexpected situations demanding rapid motor responses adapted to environmental context. The implications of this idea for current and future research are discussed.
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Affiliation(s)
- Gonçalo Lopes
- Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, United Kingdom
- NeuroGEARS Ltd., London, United Kingdom
| | - Joana Nogueira
- Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, United Kingdom
- NeuroGEARS Ltd., London, United Kingdom
| | - George Dimitriadis
- Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, United Kingdom
| | - Jorge Aurelio Menendez
- Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, United Kingdom
- Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom
- Centre for Computation, Mathematics and Physics in the Life Sciences and Experimental Biology, University College London, London, United Kingdom
| | - Joseph J. Paton
- Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Adam R. Kampff
- Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, United Kingdom
- Voight-Kampff Ltd., London, United Kingdom
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24
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Schading S, David G, Max Emmenegger T, Achim C, Thompson A, Weiskopf N, Curt A, Freund P. Dynamics of progressive degeneration of major spinal pathways following spinal cord injury: A longitudinal study. Neuroimage Clin 2023; 37:103339. [PMID: 36758456 PMCID: PMC9939725 DOI: 10.1016/j.nicl.2023.103339] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 12/23/2022] [Accepted: 01/26/2023] [Indexed: 02/04/2023]
Abstract
BACKGROUND Following spinal cord injury (SCI), disease processes spread gradually along the spinal cord forming a spatial gradient with most pronounced changes located at the lesion site. However, the dynamics of this gradient in SCI patients is not established. OBJECTIVE This study tracks the spatiotemporal dynamics of remote anterograde and retrograde spinal tract degeneration in the upper cervical cord following SCI over two years utilizing quantitative MRI. METHODS Twenty-three acute SCI patients (11 paraplegics, 12 tetraplegics) and 21 healthy controls were scanned with a T1-weighted sequence for volumetry and a FLASH sequence for myelin-sensitive magnetization transfer saturation (MTsat) of the upper cervical cord. We estimated myelin content from MTsat maps within the corticospinal tracts (CST) and dorsal columns (DC) and measured spinal cord atrophy by means of left-right width (LRW) and anterior-posterior width (APW) on the T1-weighted images across cervical levels C1-C3. MTsat in the CST and LRW were considered proxies for retrograde degeneration, while MTsat in the DC and APW provided evidence for anterograde degeneration, respectively. Using regression models, we compared the temporal and spatial trajectories of these MRI readouts between tetraplegics, paraplegics, and controls over a 2-year period and assessed their associations with clinical improvement. RESULTS Linear rates and absolute differences in myelin-sensitive MTsat indicated retrograde and anterograde neurodegeneration in the CST and DC, respectively. Changes in MTsat within the CST and in LRW progressively developed over time forming a gradient towards lower cervical levels by 2 years after injury, especially in tetraplegics (change per cervical level in MTsat: -0.247 p.u./level, p = 0.034; in LRW: -0.323 mm/level, p = 0.024). MTsat within the DC was already decreased at cervical levels C1-C3 at baseline (1.5 months after injury) in both tetra- and paraplegics, while linear decreases in APW over time were similar across C1-C3, preserving the spatial gradient. The relative improvement in light touch score was associated with MTsat within the DC at baseline (rs = 0.575, p = 0.014). CONCLUSION Rostral and remote to the injury, the CST and DC show ongoing structural changes, indicative of myelin reductions and atrophy within 2 years after SCI. While anterograde degeneration in the DC was already detectable uniformly at C1-C3 early following SCI, retrograde degeneration in the CST developed over time revealing specific spatial and temporal neurodegenerative gradients. Disentangling and quantifying such dynamic pathological processes may provide biomarkers for regenerative and remyelinating therapies along entire spinal pathways.
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Affiliation(s)
- Simon Schading
- Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland
| | - Gergely David
- Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland
| | - Tim Max Emmenegger
- Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland
| | - Cristian Achim
- Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland
| | - Alan Thompson
- Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, University College London, London, UK
| | - Nikolaus Weiskopf
- Department of Neurophysics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Felix Bloch Institute for Solid State Physics, Faculty of Physics and Earth Sciences, Leipzig University, Leipzig, Germany
| | - Armin Curt
- Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland
| | - Patrick Freund
- Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland; Department of Neurophysics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Wellcome Trust Centre for Neuroimaging, UCL Queen Square Institute of Neurology, University College London, London, UK.
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25
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Bratkowski M, Burdett TC, Danao J, Wang X, Mathur P, Gu W, Beckstead JA, Talreja S, Yang YS, Danko G, Park JH, Walton M, Brown SP, Tegley CM, Joseph PRB, Reynolds CH, Sambashivan S. Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease. Neuron 2022; 110:3711-3726.e16. [PMID: 36087583 DOI: 10.1016/j.neuron.2022.08.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 07/06/2022] [Accepted: 08/10/2022] [Indexed: 12/15/2022]
Abstract
Axon degeneration is an early pathological event in many neurological diseases. The identification of the nicotinamide adenine dinucleotide (NAD) hydrolase SARM1 as a central metabolic sensor and axon executioner presents an exciting opportunity to develop novel neuroprotective therapies that can prevent or halt the degenerative process, yet limited progress has been made on advancing efficacious inhibitors. We describe a class of NAD-dependent active-site SARM1 inhibitors that function by intercepting NAD hydrolysis and undergoing covalent conjugation with the reaction product adenosine diphosphate ribose (ADPR). The resulting small-molecule ADPR adducts are highly potent and confer compelling neuroprotection in preclinical models of neurological injury and disease, validating this mode of inhibition as a viable therapeutic strategy. Additionally, we show that the most potent inhibitor of CD38, a related NAD hydrolase, also functions by the same mechanism, further underscoring the broader applicability of this mechanism in developing therapies against this class of enzymes.
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Affiliation(s)
| | - Thomas C Burdett
- Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA
| | - Jean Danao
- Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA
| | - Xidao Wang
- Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA
| | - Prakhyat Mathur
- Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA
| | - Weijing Gu
- Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA
| | | | - Santosh Talreja
- Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA
| | - Yu-San Yang
- Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA
| | - Gregory Danko
- Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA
| | - Jae Hong Park
- Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA
| | - Mary Walton
- Chemistry Department, Nura Bio Inc., South San Francisco, CA 94080, USA
| | - Sean P Brown
- Chemistry Department, Nura Bio Inc., South San Francisco, CA 94080, USA
| | | | - Prem Raj B Joseph
- WuXi AppTec, Research Services Division, 6 Cedarbrook Drive, Cranbury, NJ 08512, USA
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26
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Barbara JG. The concept of tissue regeneration: Epistemological and historical enquiry from early ideas on the regeneration of bone to the microscopic observations of the regeneration of peripheral nerves. Front Cell Dev Biol 2022; 10:742764. [PMID: 36393844 PMCID: PMC9644045 DOI: 10.3389/fcell.2022.742764] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/21/2022] [Indexed: 09/08/2024] Open
Abstract
This paper examines the epistemological history of physiological tissue regeneration theories from Antiquity to the present time focusing on early clinical observations, microscopic investigations of the 19th C. and molecular aspects of the regeneration of peripheral nerves. We aim to show underlying theoretical implications at stake over centuries, with an extreme diversity of local contexts, while slowly emerging ideas were progressively built in the framework of cell theory and that of molecular biology. The overall epistemological lesson is that this long history is far from finished and requires novel experiments and perspectives, as well as the careful inspection of its rich past, as a true scientific tradition, in order to better understand what is nervous regeneration and how we can use it in medicine.
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Affiliation(s)
- Jean-Gaël Barbara
- Sorbonne Université, UPMC Université Paris 06, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine, UMR CNRS 8246, Inserm 1130 & Sorbonne Paris Cité, Paris Diderot, Philosophie, Histoire, SPHERE, CNRS UMR7219, Paris, France
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27
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Arena KA, Zhu Y, Kucenas S. Transforming growth factor-beta signaling modulates perineurial glial bridging following peripheral spinal motor nerve injury in zebrafish. Glia 2022; 70:1826-1849. [PMID: 35616185 PMCID: PMC9378448 DOI: 10.1002/glia.24220] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 05/06/2022] [Accepted: 05/11/2022] [Indexed: 11/12/2022]
Abstract
Spinal motor nerves are necessary for organismal locomotion and survival. In zebrafish and most vertebrates, these peripheral nervous system structures are composed of bundles of axons that naturally regenerate following injury. However, the cellular and molecular mechanisms that mediate this process are still only partially understood. Perineurial glia, which form a component of the blood-nerve barrier, are necessary for the earliest regenerative steps by establishing a glial bridge across the injury site as well as phagocytosing debris. Without perineurial glial bridging, regeneration is impaired. In addition to perineurial glia, Schwann cells, the cells that ensheath and myelinate axons within the nerve, are essential for debris clearance and axon guidance. In the absence of Schwann cells, perineurial glia exhibit perturbed bridging, demonstrating that these two cell types communicate during the injury response. While the presence and importance of perineurial glial bridging is known, the molecular mechanisms that underlie this process remain a mystery. Understanding the cellular and molecular interactions that drive perineurial glial bridging is crucial to unlocking the mechanisms underlying successful motor nerve regeneration. Using laser axotomy and in vivo imaging in zebrafish, we show that transforming growth factor-beta (TGFβ) signaling modulates perineurial glial bridging. Further, we identify connective tissue growth factor-a (ctgfa) as a downstream effector of TGF-β signaling that works in a positive feedback loop to mediate perineurial glial bridging. Together, these studies present a new signaling pathway involved in the perineurial glial injury response and further characterize the dynamics of the perineurial glial bridge.
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Affiliation(s)
- Kimberly A. Arena
- Department of BiologyUniversity of VirginiaCharlottesvilleVirginiaUSA
- Program in Fundamental NeuroscienceUniversity of VirginiaCharlottesvilleVirginiaUSA
| | - Yunlu Zhu
- Department of BiologyUniversity of VirginiaCharlottesvilleVirginiaUSA
| | - Sarah Kucenas
- Department of BiologyUniversity of VirginiaCharlottesvilleVirginiaUSA
- Program in Fundamental NeuroscienceUniversity of VirginiaCharlottesvilleVirginiaUSA
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28
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von Mikecz A. Exposome, Molecular Pathways and One Health: The Invertebrate Caenorhabditis elegans. Int J Mol Sci 2022; 23:9084. [PMID: 36012346 PMCID: PMC9409025 DOI: 10.3390/ijms23169084] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 12/04/2022] Open
Abstract
Due to its preferred habitats in the environment, the free-living nematode Caenorhabditis elegans has become a realistic target organism for pollutants, including manufactured nanoparticles. In the laboratory, the invertebrate animal model represents a cost-effective tool to investigate the molecular mechanisms of the biological response to nanomaterials. With an estimated number of 22,000 coding genes and short life span of 2-3 weeks, the small worm is a giant when it comes to characterization of molecular pathways, long-term low dose pollutant effects and vulnerable age-groups. Here, we review (i) flows of manufactured nanomaterials and exposition of C. elegans in the environment, (ii) the track record of C. elegans in biomedical research, and (iii) its potential to contribute to the investigation of the exposome and bridge nanotoxicology between higher organisms, including humans. The role of C. elegans in the one health concept is taken one step further by proposing methods to sample wild nematodes and their molecular characterization by single worm proteomics.
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Affiliation(s)
- Anna von Mikecz
- IUF-Leibniz Research Institute for Environmental Medicine GmbH, Auf'm Hennekamp 50, 40225 Duesseldorf, Germany
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29
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Tapia ML, Nascimento-Dos-Santos G, Park KK. Subtype-specific survival and regeneration of retinal ganglion cells in response to injury. Front Cell Dev Biol 2022; 10:956279. [PMID: 36035999 PMCID: PMC9411869 DOI: 10.3389/fcell.2022.956279] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 06/28/2022] [Indexed: 11/19/2022] Open
Abstract
Retinal ganglion cells (RGCs) are a heterogeneous population of neurons that function synchronously to convey visual information through the optic nerve to retinorecipient target areas in the brain. Injury or disease to the optic nerve results in RGC degeneration and loss of visual function, as few RGCs survive, and even fewer can be provoked to regenerate their axons. Despite causative insults being broadly shared, regeneration studies demonstrate that RGC types exhibit differential resilience to injury and undergo selective survival and regeneration of their axons. While most early studies have identified these RGC types based their morphological and physiological characteristics, recent advances in transgenic and gene sequencing technologies have further enabled type identification based on unique molecular features. In this review, we provide an overview of the well characterized RGC types and identify those shown to preferentially survive and regenerate in various regeneration models. Furthermore, we discuss cellular characteristics of both the resilient and susceptible RGC types including the combinatorial expression of different molecular markers that identify these specific populations. Lastly, we discuss potential molecular mechanisms and genes found to be selectively expressed by specific types that may contribute to their reparative capacity. Together, we describe the studies that lay the important groundwork for identifying factors that promote neural regeneration and help advance the development of targeted therapy for the treatment of RGC degeneration as well as neurodegenerative diseases in general.
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Affiliation(s)
- Mary L Tapia
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Gabriel Nascimento-Dos-Santos
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Kevin K Park
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, United States
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30
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Rosenbaum T, Morales-Lázaro SL, Islas LD. TRP channels: a journey towards a molecular understanding of pain. Nat Rev Neurosci 2022; 23:596-610. [PMID: 35831443 DOI: 10.1038/s41583-022-00611-7] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2022] [Indexed: 12/18/2022]
Abstract
The perception of nociceptive signals, which are translated into pain, plays a fundamental role in the survival of organisms. Because pain is linked to a negative sensation, animals learn to avoid noxious signals. These signals are detected by receptors, which include some members of the transient receptor potential (TRP) family of ion channels that act as transducers of exogenous and endogenous noxious cues. These proteins have been in the focus of the field of physiology for several years, and much knowledge of how they regulate the function of the cell types and organs where they are expressed has been acquired. The last decade has been especially exciting because the 'resolution revolution' has allowed us to learn the molecular intimacies of TRP channels using cryogenic electron microscopy. These findings, in combination with functional studies, have provided insights into the role played by these channels in the generation and maintenance of pain.
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Affiliation(s)
- Tamara Rosenbaum
- Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, UNAM, Mexico City, Mexico.
| | - Sara L Morales-Lázaro
- Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, UNAM, Mexico City, Mexico
| | - León D Islas
- Departamento de Fisiología, Facultad de Medicina, UNAM, Mexico City, Mexico
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31
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Osorio-Méndez D, Miller A, Begeman IJ, Kurth A, Hagle R, Rolph D, Dickson AL, Chen CH, Halloran M, Poss KD, Kang J. Voltage-gated sodium channel scn8a is required for innervation and regeneration of amputated adult zebrafish fins. Proc Natl Acad Sci U S A 2022; 119:e2200342119. [PMID: 35867745 PMCID: PMC9282381 DOI: 10.1073/pnas.2200342119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 05/10/2022] [Indexed: 01/09/2023] Open
Abstract
Teleost fishes and urodele amphibians can regenerate amputated appendages, whereas this ability is restricted to digit tips in adult mammals. One key component of appendage regeneration is reinnervation of the wound area. However, how innervation is regulated in injured appendages of adult vertebrates has seen limited research attention. From a forward genetics screen for temperature-sensitive defects in zebrafish fin regeneration, we identified a mutation that disrupted regeneration while also inducing paralysis at the restrictive temperature. Genetic mapping and complementation tests identify a mutation in the major neuronal voltage-gated sodium channel (VGSC) gene scn8ab. Conditional disruption of scn8ab impairs early regenerative events, including blastema formation, but does not affect morphogenesis of established regenerates. Whereas scn8ab mutations reduced neural activity as expected, they also disrupted axon regrowth and patterning in fin regenerates, resulting in hypoinnervation. Our findings indicate that the activity of VGSCs plays a proregenerative role by promoting innervation of appendage stumps.
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Affiliation(s)
- Daniel Osorio-Méndez
- Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI 53705
| | - Andrew Miller
- Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI 53705
- Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705
| | - Ian J. Begeman
- Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI 53705
| | - Andrew Kurth
- Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI 53705
| | - Ryan Hagle
- Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI 53705
| | - Daniela Rolph
- Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI 53705
| | - Amy L. Dickson
- Duke Regeneration Center, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710
| | - Chen-Hui Chen
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan
| | - Mary Halloran
- Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI 53705
- Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705
| | - Kenneth D. Poss
- Duke Regeneration Center, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710
| | - Junsu Kang
- Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI 53705
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32
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Herrmann KA, Liu Y, Llobet-Rosell A, McLaughlin CN, Neukomm LJ, Coutinho-Budd JC, Broihier HT. Divergent signaling requirements of dSARM in injury-induced degeneration and developmental glial phagocytosis. PLoS Genet 2022; 18:e1010257. [PMID: 35737721 PMCID: PMC9223396 DOI: 10.1371/journal.pgen.1010257] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 05/13/2022] [Indexed: 02/06/2023] Open
Abstract
Elucidating signal transduction mechanisms of innate immune pathways is essential to defining how they elicit distinct cellular responses. Toll-like receptors (TLR) signal through their cytoplasmic TIR domains which bind other TIR domain-containing adaptors. dSARM/SARM1 is one such TIR domain adaptor best known for its role as the central axon degeneration trigger after injury. In degeneration, SARM1's domains have been assigned unique functions: the ARM domain is auto-inhibitory, SAM-SAM domain interactions mediate multimerization, and the TIR domain has intrinsic NAD+ hydrolase activity that precipitates axonal demise. Whether and how these distinct functions contribute to TLR signaling is unknown. Here we show divergent signaling requirements for dSARM in injury-induced axon degeneration and TLR-mediated developmental glial phagocytosis through analysis of new knock-in domain and point mutations. We demonstrate intragenic complementation between reciprocal pairs of domain mutants during development, providing evidence for separability of dSARM functional domains in TLR signaling. Surprisingly, dSARM's NAD+ hydrolase activity is strictly required for both degenerative and developmental signaling, demonstrating that TLR signal transduction requires dSARM's enzymatic activity. In contrast, while SAM domain-mediated dSARM multimerization is important for axon degeneration, it is dispensable for TLR signaling. Finally, dSARM functions in a linear genetic pathway with the MAP3K Ask1 during development but not in degenerating axons. Thus, we propose that dSARM exists in distinct signaling states in developmental and pathological contexts.
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Affiliation(s)
- Kelsey A. Herrmann
- Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Yizhou Liu
- Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Arnau Llobet-Rosell
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Colleen N. McLaughlin
- Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Lukas J. Neukomm
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Jaeda C. Coutinho-Budd
- Department of Neuroscience, University of Virginia, Charlottesville, Virginia, United States of America
| | - Heather T. Broihier
- Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- * E-mail:
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33
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Adler M, Pellett S, Sharma SK, Lebeda FJ, Dembek ZF, Mahan MA. Preclinical Evidence for the Role of Botulinum Neurotoxin A (BoNT/A) in the Treatment of Peripheral Nerve Injury. Microorganisms 2022; 10:microorganisms10050886. [PMID: 35630331 PMCID: PMC9148055 DOI: 10.3390/microorganisms10050886] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 03/29/2022] [Accepted: 04/17/2022] [Indexed: 01/27/2023] Open
Abstract
Traumatic peripheral nerve injuries tend to be more common in younger, working age populations and can lead to long-lasting disability. Peripheral nerves have an impressive capacity to regenerate; however, successful recovery after injury depends on a number of factors including the mechanism and severity of the trauma, the distance from injury to the reinnervation target, connective tissue sheath integrity, and delay between injury and treatment. Even though modern surgical procedures have greatly improved the success rate, many peripheral nerve injuries still culminate in persistent neuropathic pain and incomplete functional recovery. Recent studies in animals suggest that botulinum neurotoxin A (BoNT/A) can accelerate nerve regeneration and improve functional recovery after injury to peripheral nerves. Possible mechanisms of BoNT/A action include activation or proliferation of support cells (Schwann cells, mast cells, and macrophages), increased angiogenesis, and improvement of blood flow to regenerating nerves.
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Affiliation(s)
- Michael Adler
- Neuroscience Department, Medical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd., Aberdeen Proving Ground, MD 21010, USA
- Correspondence: ; Tel.: +1-410-436-1913
| | - Sabine Pellett
- Department of Bacteriology, University of Wisconsin-Madison, 1550 Linden Drive, Madison, WI 53706, USA;
| | - Shashi K. Sharma
- Division of Microbiology, Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD 20740, USA;
| | - Frank J. Lebeda
- Biotechnology, Protein Bioinformatics, Zanvyl Krieger School of Arts & Sciences, Johns Hopkins University, Advanced Academic Programs, 9601 Medical Center Drive, Rockville, MD 20850, USA;
| | - Zygmunt F. Dembek
- Department of Military and Emergency Medicine, Uniformed Services University of Health Sciences, 3154 Jones Bridge Rd., Bethesda, MD 20814, USA;
| | - Mark A. Mahan
- Department of Neurosurgery, Clinical Neurosciences, University of Utah, 175 N Medical Drive East, Salt Lake City, UT 84132, USA;
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34
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Cao Y, Wang Y, Yang J. NAD +-dependent mechanism of pathological axon degeneration. CELL INSIGHT 2022; 1:100019. [PMID: 37193131 PMCID: PMC10120281 DOI: 10.1016/j.cellin.2022.100019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 05/18/2023]
Abstract
Pathological axon degeneration is broadly observed in neurodegenerative diseases. This unique process of axonal pathology could directly interfere with the normal functions of neurocircuitries and contribute to the onset of clinical symptoms in patients. It has been increasingly recognized that functional preservation of axonal structures is an indispensable part of therapeutic strategies for treating neurological disorders. In the past decades, the research field has witnessed significant breakthroughs in understanding the stereotyped self-destruction of axons upon neurodegenerative insults, which is distinct from all the known types of programmed cell death. In particular, the novel NAD+-dependent mechanism involving the WLDs, NMNAT2, and SARM1 proteins has emerged. This review summarizes the landmark discoveries elucidating the molecular pathway of pathological axon degeneration and highlights the evolving concept that neurodegeneration would be intrinsically linked to NAD+ and energy metabolism.
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Affiliation(s)
- Ying Cao
- Center for Life Sciences, Peking University, Beijing, 100871, China
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Yi Wang
- Center for Life Sciences, Peking University, Beijing, 100871, China
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Jing Yang
- Center for Life Sciences, Peking University, Beijing, 100871, China
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
- IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China
- Chinese Institute for Brain Research, Beijing, 102206, China
- Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, 518055, China
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35
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Pellegatta M, Canevazzi P, Forese MG, Podini P, Valenzano S, Del Carro U, Quattrini A, Taveggia C. ADAM17 Regulates p75 NTR-Mediated Fibrinolysis and Nerve Remyelination. J Neurosci 2022; 42:2433-2447. [PMID: 35110388 PMCID: PMC8944234 DOI: 10.1523/jneurosci.1341-21.2022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 11/12/2021] [Accepted: 01/03/2022] [Indexed: 11/21/2022] Open
Abstract
We previously reported that a-disintegrin and metalloproteinase (ADAM)17 is a key protease regulating myelin formation. We now describe a role for ADAM17 during the Wallerian degeneration (WD) process. Unexpectedly, we observed that glial ADAM17, by regulating p75NTR processing, cell autonomously promotes remyelination, while neuronal ADAM17 is dispensable. Accordingly, p75NTR abnormally accumulates specifically when ADAM17 is maximally expressed leading to a downregulation of tissue plasminogen activator (tPA) expression, excessive fibrin accumulation over time, and delayed remyelination. Mutant mice also present impaired macrophage recruitment and defective nerve conduction velocity (NCV). Thus, ADAM17 expressed in Schwann cells, controls the whole WD process, and its absence hampers effective nerve repair. Collectively, we describe a previously uncharacterized role for glial ADAM17 during nerve regeneration. Based on the results of our study, we posit that, unlike development, glial ADAM17 promotes remyelination through the regulation of p75NTR-mediated fibrinolysis.SIGNIFICANCE STATEMENT The α-secretase a-disintegrin and metalloproteinase (ADAM)17, although relevant for developmental PNS myelination, has never been investigated in Wallerian degeneration (WD). We now unravel a new mechanism of action for this protease and show that ADAM17 cleaves p75NTR, regulates fibrin clearance, and eventually fine-tunes remyelination. The results presented in this study provide important insights into the complex regulation of remyelination following nerve injury, identifying in ADAM17 and p75NTR a new signaling axis implicated in these events. Modulation of this pathway could have important implications in promoting nerve remyelination, an often-inefficient process, with the aim of restoring a functional axo-glial unit.
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Affiliation(s)
- Marta Pellegatta
- Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Research Hospital, Milan 20132, Italy
| | - Paolo Canevazzi
- Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Research Hospital, Milan 20132, Italy
| | - Maria Grazia Forese
- Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Research Hospital, Milan 20132, Italy
| | - Paola Podini
- Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Research Hospital, Milan 20132, Italy
| | - Serena Valenzano
- Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Research Hospital, Milan 20132, Italy
| | - Ubaldo Del Carro
- Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Research Hospital, Milan 20132, Italy
| | - Angelo Quattrini
- Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Research Hospital, Milan 20132, Italy
| | - Carla Taveggia
- Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Research Hospital, Milan 20132, Italy
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36
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Ernst J, Weiss T, Wanke N, Frahm J, Felmerer G, Farina D, Schilling AF, Wilke MA. Case Report: Plasticity in Central Sensory Finger Representation and Touch Perception After Microsurgical Reconstruction of Infraclavicular Brachial Plexus Injury. Front Neurosci 2022; 16:793036. [PMID: 35281503 PMCID: PMC8914191 DOI: 10.3389/fnins.2022.793036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/26/2022] [Indexed: 11/13/2022] Open
Abstract
After brachial plexus injury (BPI), early microsurgery aims at facilitating reconnection of the severed peripheral nerves with their orphan muscles and sensory receptors and thereby reestablishing communication with the brain. In order to investigate this sensory recovery, here we combined functional magnetic resonance imaging (fMRI) and tactile psychophysics in a patient who suffered a sharp, incomplete amputation of the dominant hand at the axilla level. To determine somatosensory detection and discomfort thresholds as well as sensory accuracy for fingers of both the intact and affected hand, we used electrotactile stimulation in the framework of a mislocalization test. Additionally, tactile stimulation was performed in the MRI scanner in order to determine the cortical organization of the possibly affected primary somatosensory cortex. The patient was able to detect electrotactile stimulation in 4 of the 5 fingertips (D1, D2, D4, D5), and in the middle phalanx in D3 indicating some innervation. The detection and discomfort threshold were considerably higher at the affected side than at the intact side, with higher detection and discomfort thresholds for the affected side. The discrimination accuracy was rather low at the affected side, with stimulation of D1/D2/D3/D4/D5 eliciting most commonly a sensation at D4/D1/D3/D2/D5, respectively. The neuroimaging data showed a mediolateral succession from D2 to D5 to D1 to D4 (no activation was observed for D3). These results indicate a successful regrowth of the peripheral nerve fibers from the axilla to four fingertips. The data suggest that some of the fibers have switched location in the process and there is a beginning of cortical reorganization in the primary somatosensory cortex, possibly resulting from a re-education of the brain due to conflicting information (touch vs. vision).
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Affiliation(s)
- Jennifer Ernst
- Department of Trauma Surgery, Orthopaedics, and Plastic Surgery, Universitätsmedizin Göttingen, Göttingen, Germany
- *Correspondence: Jennifer Ernst
| | - Thomas Weiss
- Clinical Psychology, Friedrich Schiller University Jena, Jena, Germany
| | - Nadine Wanke
- Fakultät Life Sciences, Hamburg University of Applied Sciences (HAW Hamburg), Hamburg, Germany
| | - Jens Frahm
- Biomedizinische Nuclear Magnetic Resonance (NMR) Forschungs-GmbH am Max-Planck-Institut für biophysikalische Chemie, Göttingen, Germany
| | - Gunther Felmerer
- Department of Trauma Surgery, Orthopaedics, and Plastic Surgery, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Dario Farina
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | - Arndt F. Schilling
- Department of Trauma Surgery, Orthopaedics, and Plastic Surgery, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Meike A. Wilke
- Department of Trauma Surgery, Orthopaedics, and Plastic Surgery, Universitätsmedizin Göttingen, Göttingen, Germany
- Fakultät Life Sciences, Hamburg University of Applied Sciences (HAW Hamburg), Hamburg, Germany
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Ji H, Sapar ML, Sarkar A, Wang B, Han C. Phagocytosis and self-destruction break down dendrites of Drosophila sensory neurons at distinct steps of Wallerian degeneration. Proc Natl Acad Sci U S A 2022; 119:e2111818119. [PMID: 35058357 PMCID: PMC8795528 DOI: 10.1073/pnas.2111818119] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 12/01/2021] [Indexed: 12/12/2022] Open
Abstract
After injury, severed dendrites and axons expose the "eat-me" signal phosphatidylserine (PS) on their surface while they break down. The degeneration of injured axons is controlled by a conserved Wallerian degeneration (WD) pathway, which is thought to activate neurite self-destruction through Sarm-mediated nicotinamide adenine dinucleotide (NAD+) depletion. While neurite PS exposure is known to be affected by genetic manipulations of NAD+, how the WD pathway coordinates both neurite PS exposure and self-destruction and whether PS-induced phagocytosis contributes to neurite breakdown in vivo remain unknown. Here, we show that in Drosophila sensory dendrites, PS exposure and self-destruction are two sequential steps of WD resulting from Sarm activation. Surprisingly, phagocytosis is the main driver of dendrite degeneration induced by both genetic NAD+ disruptions and injury. However, unlike neuronal Nmnat loss, which triggers PS exposure only and results in phagocytosis-dependent dendrite degeneration, injury activates both PS exposure and self-destruction as two redundant means of dendrite degeneration. Furthermore, the axon-death factor Axed is only partially required for self-destruction of injured dendrites, acting in parallel with PS-induced phagocytosis. Lastly, injured dendrites exhibit a unique rhythmic calcium-flashing that correlates with WD. Therefore, both NAD+-related general mechanisms and dendrite-specific programs govern PS exposure and self-destruction in injury-induced dendrite degeneration in vivo.
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Affiliation(s)
- Hui Ji
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
| | - Maria L Sapar
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
| | - Ankita Sarkar
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
| | - Bei Wang
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
| | - Chun Han
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853;
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
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Abstract
Traumatic injury of the central nervous system (CNS) is a worldwide health problem affecting millions of people. Trauma of the CNS, that is, traumatic brain injury (TBI) and spinal cord injury (SCI), lead to massive and progressive cell loss and axonal degeneration, usually with very limited regeneration. At present, there are no treatments to protect injured CNS tissue or to replace the lost tissue. Stem cells are a cell type that by definition can self-renew and give rise to multiple cell lineages. In recent years, therapies using stem and progenitor cells have shown promising effects in experimental CNS trauma, particularly in the acute-subacute stage, but also in chronic injuries. However, the therapeutic mechanisms by which transplanted cells achieve the structural and/or functional improvements are often not clear. Stem cell therapies for CNS trauma can be categorized into 2 main concepts, transplantation of exogenous neural stem cells and neural progenitor cells and recruitment of endogenous stem and progenitor cells. In this review, focusing on the advances during the last decade, we will discuss the major cell therapies, the pros and cons of these 2 concepts for TBI and SCI, and the treatment strategies we believe will be successful.
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Affiliation(s)
- Xiaofei Li
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Erik Sundström
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Corresponding author: Erik Sundström, Department of Neurobiology, Care Sciences and Society (NVS), BioClinicum J9:20, Karolinska University Hospital, S17164 Solna, Sweden.
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Wofford KL, Shultz RB, Burrell JC, Cullen DK. Neuroimmune interactions and immunoengineering strategies in peripheral nerve repair. Prog Neurobiol 2022; 208:102172. [PMID: 34492307 PMCID: PMC8712351 DOI: 10.1016/j.pneurobio.2021.102172] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/11/2021] [Accepted: 09/02/2021] [Indexed: 01/03/2023]
Abstract
Peripheral nerve injuries result in disrupted cellular communication between the central nervous system and somatic distal end targets. The peripheral nervous system is capable of independent and extensive regeneration; however, meaningful target muscle reinnervation and functional recovery remain limited and may result in chronic neuropathic pain and diminished quality of life. Macrophages, the primary innate immune cells of the body, are critical contributors to regeneration of the injured peripheral nervous system. However, in some clinical scenarios, macrophages may fail to provide adequate support with optimal timing, duration, and location. Here, we review the history of immunosuppressive and immunomodulatory strategies to treat nerve injuries. Thereafter, we enumerate the ways in which macrophages contribute to successful nerve regeneration. We argue that implementing macrophage-based immunomodulatory therapies is a promising treatment strategy for nerve injuries across a wide range of clinical presentations.
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Affiliation(s)
- Kathryn L Wofford
- Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, 19104, United States; Center for Neurotrauma, Neurodegeneration and Restoration, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, 19104, United States
| | - Robert B Shultz
- Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, 19104, United States; Center for Neurotrauma, Neurodegeneration and Restoration, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, 19104, United States; Axonova Medical, LLC, Philadelphia, PA, 19104, United States
| | - Justin C Burrell
- Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, 19104, United States; Center for Neurotrauma, Neurodegeneration and Restoration, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, 19104, United States; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, United States
| | - D Kacy Cullen
- Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, 19104, United States; Center for Neurotrauma, Neurodegeneration and Restoration, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, 19104, United States; Axonova Medical, LLC, Philadelphia, PA, 19104, United States; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, United States.
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40
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Sardella-Silva G, Mietto BS, Ribeiro-Resende VT. Four Seasons for Schwann Cell Biology, Revisiting Key Periods: Development, Homeostasis, Repair, and Aging. Biomolecules 2021; 11:1887. [PMID: 34944531 PMCID: PMC8699407 DOI: 10.3390/biom11121887] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/08/2021] [Accepted: 12/10/2021] [Indexed: 01/28/2023] Open
Abstract
Like the seasons of the year, all natural things happen in stages, going through adaptations when challenged, and Schwann cells are a great example of that. During maturation, these cells regulate several steps in peripheral nervous system development. The Spring of the cell means the rise and bloom through organized stages defined by time-dependent regulation of factors and microenvironmental influences. Once matured, the Summer of the cell begins: a high energy stage focused on maintaining adult homeostasis. The Schwann cell provides many neuron-glia communications resulting in the maintenance of synapses. In the peripheral nervous system, Schwann cells are pivotal after injuries, balancing degeneration and regeneration, similarly to when Autumn comes. Their ability to acquire a repair phenotype brings the potential to reconnect axons to targets and regain function. Finally, Schwann cells age, not only by growing old, but also by imposed environmental cues, like loss of function induced by pathologies. The Winter of the cell presents as reduced activity, especially regarding their role in repair; this reflects on the regenerative potential of older/less healthy individuals. This review gathers essential information about Schwann cells in different stages, summarizing important participation of this intriguing cell in many functions throughout its lifetime.
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Affiliation(s)
- Gabriela Sardella-Silva
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil;
- Núcleo Multidisciplinar de Pesquisa em Biologia (Numpex-Bio), Campus de Duque de Caxias Geraldo Guerra Cidade, Universidade Federal do Rio de Janeiro, Duque de Caxias 25255-030, RJ, Brazil
| | - Bruno Siqueira Mietto
- Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Juiz de Fora 36036-900, MG, Brazil;
| | - Victor Túlio Ribeiro-Resende
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil;
- Núcleo Multidisciplinar de Pesquisa em Biologia (Numpex-Bio), Campus de Duque de Caxias Geraldo Guerra Cidade, Universidade Federal do Rio de Janeiro, Duque de Caxias 25255-030, RJ, Brazil
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Linsley JW, Linsley DA, Lamstein J, Ryan G, Shah K, Castello NA, Oza V, Kalra J, Wang S, Tokuno Z, Javaherian A, Serre T, Finkbeiner S. Superhuman cell death detection with biomarker-optimized neural networks. SCIENCE ADVANCES 2021; 7:eabf8142. [PMID: 34878844 PMCID: PMC8654296 DOI: 10.1126/sciadv.abf8142] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 10/19/2021] [Indexed: 05/02/2023]
Abstract
Cellular events underlying neurodegenerative disease may be captured by longitudinal live microscopy of neurons. While the advent of robot-assisted microscopy has helped scale such efforts to high-throughput regimes with the statistical power to detect transient events, time-intensive human annotation is required. We addressed this fundamental limitation with biomarker-optimized convolutional neural networks (BO-CNNs): interpretable computer vision models trained directly on biosensor activity. We demonstrate the ability of BO-CNNs to detect cell death, which is typically measured by trained annotators. BO-CNNs detected cell death with superhuman accuracy and speed by learning to identify subcellular morphology associated with cell vitality, despite receiving no explicit supervision to rely on these features. These models also revealed an intranuclear morphology signal that is difficult to spot by eye and had not previously been linked to cell death, but that reliably indicates death. BO-CNNs are broadly useful for analyzing live microscopy and essential for interpreting high-throughput experiments.
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Affiliation(s)
- Jeremy W. Linsley
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Drew A. Linsley
- Robert J. & Nancy D. Carney Institute for Brain Science, Brown University, Providence, RI 02912, USA
- Department of Cognitive, Linguistic & Psychological Sciences, Brown University, Providence, RI 02912, USA
| | - Josh Lamstein
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Gennadi Ryan
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Kevan Shah
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Nicholas A. Castello
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Viral Oza
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Jaslin Kalra
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Shijie Wang
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Zachary Tokuno
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Ashkan Javaherian
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Thomas Serre
- Robert J. & Nancy D. Carney Institute for Brain Science, Brown University, Providence, RI 02912, USA
- Department of Cognitive, Linguistic & Psychological Sciences, Brown University, Providence, RI 02912, USA
| | - Steven Finkbeiner
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
- Taube/Koret Center for Neurodegenerative Disease, Gladstone Institutes, San Francisco, CA 94158, USA
- Departments of Neurology and Physiology, University of California, San Francisco, San Francisco, CA 94158, USA
- Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA
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42
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Arthur-Farraj P, Coleman MP. Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases. Neurotherapeutics 2021; 18:2200-2221. [PMID: 34595734 PMCID: PMC8804151 DOI: 10.1007/s13311-021-01125-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2021] [Indexed: 12/25/2022] Open
Abstract
Since Waller and Cajal in the nineteenth and early twentieth centuries, laboratory traumatic peripheral nerve injury studies have provided great insight into cellular and molecular mechanisms governing axon degeneration and the responses of Schwann cells, the major glial cell type of peripheral nerves. It is now evident that pathways underlying injury-induced axon degeneration and the Schwann cell injury-specific state, the repair Schwann cell, are relevant to many inherited and acquired disorders of peripheral nerves. This review provides a timely update on the molecular understanding of axon degeneration and formation of the repair Schwann cell. We discuss how nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and sterile alpha TIR motif containing protein 1 (SARM1) are required for axon survival and degeneration, respectively, how transcription factor c-JUN is essential for the Schwann cell response to nerve injury and what each tells us about disease mechanisms and potential therapies. Human genetic association with NMNAT2 and SARM1 strongly suggests aberrant activation of programmed axon death in polyneuropathies and motor neuron disorders, respectively, and animal studies suggest wider involvement including in chemotherapy-induced and diabetic neuropathies. In repair Schwann cells, cJUN is aberrantly expressed in a wide variety of human acquired and inherited neuropathies. Animal models suggest it limits axon loss in both genetic and traumatic neuropathies, whereas in contrast, Schwann cell secreted Neuregulin-1 type 1 drives onion bulb pathology in CMT1A. Finally, we discuss opportunities for drug-based and gene therapies to prevent axon loss or manipulate the repair Schwann cell state to treat acquired and inherited neuropathies and neuronopathies.
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Affiliation(s)
- Peter Arthur-Farraj
- Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Robinson Way, Cambridge, CB2 0PY, UK.
| | - Michael P Coleman
- Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Robinson Way, Cambridge, CB2 0PY, UK.
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Abstract
Significant advances have been made in recent years in identifying the genetic components of Wallerian degeneration, the process that brings the progressive destruction and removal of injured axons. It has now been accepted that Wallerian degeneration is an active and dynamic cellular process that is well regulated at molecular and cellular levels. In this review, we describe our current understanding of Wallerian degeneration, focusing on the molecular players and mechanisms that mediate the injury response, activate the degenerative program, transduce the death signal, execute the destruction order, and finally, clear away the debris. By highlighting the starring roles and sketching out the molecular script of Wallerian degeneration, we hope to provide a useful framework to understand Wallerian and Wallerian-like degeneration and to lay a foundation for developing new therapeutic strategies to treat axon degeneration in neural injury as well as in neurodegenerative disease. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Kai Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China; , , .,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mingsheng Jiang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China; , , .,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yanshan Fang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China; , , .,University of Chinese Academy of Sciences, Beijing 100049, China
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44
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Shah GV. Editorial for "Functional Reorganizations Outside the Sensorimotor Regions Following Complete Thoracolumbar Spinal Cord Injury". J Magn Reson Imaging 2021; 54:1560-1561. [PMID: 34288214 DOI: 10.1002/jmri.27840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 11/06/2022] Open
Affiliation(s)
- Gaurang V Shah
- Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA
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45
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Hopkins EL, Gu W, Kobe B, Coleman MP. A Novel NAD Signaling Mechanism in Axon Degeneration and its Relationship to Innate Immunity. Front Mol Biosci 2021; 8:703532. [PMID: 34307460 PMCID: PMC8295901 DOI: 10.3389/fmolb.2021.703532] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/28/2021] [Indexed: 12/21/2022] Open
Abstract
Axon degeneration represents a pathological feature of many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease where axons die before the neuronal soma, and axonopathies, such as Charcot-Marie-Tooth disease and hereditary spastic paraplegia. Over the last two decades, it has slowly emerged that a central signaling pathway forms the basis of this process in many circumstances. This is an axonal NAD-related signaling mechanism mainly regulated by the two key proteins with opposing roles: the NAD-synthesizing enzyme NMNAT2, and SARM1, a protein with NADase and related activities. The crosstalk between the axon survival factor NMNAT2 and pro-degenerative factor SARM1 has been extensively characterized and plays an essential role in maintaining the axon integrity. This pathway can be activated in necroptosis and in genetic, toxic or metabolic disorders, physical injury and neuroinflammation, all leading to axon pathology. SARM1 is also known to be involved in regulating innate immunity, potentially linking axon degeneration to the response to pathogens and intercellular signaling. Understanding this NAD-related signaling mechanism enhances our understanding of the process of axon degeneration and enables a path to the development of drugs for a wide range of neurodegenerative diseases.
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Affiliation(s)
- Eleanor L. Hopkins
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Weixi Gu
- School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
| | - Bostjan Kobe
- School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
| | - Michael P. Coleman
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
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46
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Delibas B, Kuruoglu E, Bereket MC, Onger ME. Allantoin, a purine metabolite, enhances peripheral nerve regeneration following sciatic nerve injury in rats: A stereological and immunohistochemical study. J Chem Neuroanat 2021; 117:102002. [PMID: 34242746 DOI: 10.1016/j.jchemneu.2021.102002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 06/08/2021] [Accepted: 07/03/2021] [Indexed: 11/19/2022]
Abstract
AIM Following peripheral nerve injury, in addition to axonal and myelin degeneration, a sharp increase is observed in cell numbers, especially Schwann cells, in the distal part of the injury. This study investigated the effect of allantoin, involved in purine catabolism, on the reactions occurring in the lesion area. MATERIAL AND METHOD An experimental sciatic nerve injury model was established with the application of pressure at 50 Newtons for 5 s to the right sciatic nerves of experimental animals following visualization with the help of pliers. Allantoin was administered to the test groups via the intraperitoneal (i.p.) route (10 mg/kg), at the same time every day for 30 days. The animals were sacrificed at the end of 30 days, following electromyography and Sciatic Function Index tests. Myelinated/unmyelinated axon numbers were evaluated stereologically. Myelin sheath thickness, axon diameter, mitotic activity, and functional improvement in muscles in this peripheral nerve degeneration model were investigated. The test results were then subjected to statistical analysis. RESULTS Allantoin was observed to exhibit curative effects in terms of function, although stereological tests revealed no morphological differences. CONCLUSION The i.p. administration of allantoin may have a beneficial effect on nerve healing.
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Affiliation(s)
- Burcu Delibas
- Department of Histology and Embryology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey.
| | - Enis Kuruoglu
- Department of Neurosurgery, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey; Department of Neuroscience, Health Science Institute, Ondokuz Mayıs University, Samsun, Turkey
| | - Mehmet Cihan Bereket
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Ondokuz Mayıs University, Samsun, Turkey
| | - Mehmet Emin Onger
- Department of Histology and Embryology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey; Department of Neuroscience, Health Science Institute, Ondokuz Mayıs University, Samsun, Turkey
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47
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van Niftrik CHB, Sebök M, Muscas G, Wegener S, Luft AR, Stippich C, Regli L, Fierstra J. Investigating the Association of Wallerian Degeneration and Diaschisis After Ischemic Stroke With BOLD Cerebrovascular Reactivity. Front Physiol 2021; 12:645157. [PMID: 34248656 PMCID: PMC8264262 DOI: 10.3389/fphys.2021.645157] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 05/24/2021] [Indexed: 11/15/2022] Open
Abstract
Introduction Wallerian degeneration and diaschisis are considered separate remote entities following ischemic stroke. They may, however, share common neurophysiological denominators, since they are both related to disruption of fiber tracts and brain atrophy over time. Therefore, with advanced multimodal neuroimaging, we investigate Wallerian degeneration and its association with diaschisis. Methods In order to determine different characteristics of Wallerian degeneration, we conducted examinations on seventeen patients with chronic unilateral ischemic stroke and persisting large vessel occlusion, conducting high-resolution anatomical magnetic resonance imaging (MRI) and blood oxygenation-level dependent cerebrovascular reactivity (BOLD-CVR) tests, as well as Diamox 15(O)–H2O–PET hemodynamic examinations. Wallerian degeneration was determined using a cerebral peduncle asymmetry index (% difference of volume of ipsilateral and contralateral cerebral peduncle) of more than two standard deviations away from the average of age-matched, healthy subjects (Here a cerebral peduncle asymmetry index > 11%). Diaschisis was derived from BOLD-CVR to assess the presence of ipsilateral thalamus diaschisis and/or crossed cerebellar diaschisis. Results Wallerian degeneration, found in 8 (47%) subjects, had a strong association with ipsilateral thalamic volume reduction (r2 = 0.60) and corticospinal-tract involvement of stroke (p < 0.001). It was also associated with ipsilateral thalamic diaschisis (p = 0.021), No cerebral peduncular hemodynamic differences were found in patients with Wallerian degeneration. In particular, no CBF decrease or BOLD-CVR impairment was found. Conclusion We show a strong association between Wallerian degeneration and ipsilateral thalamic diaschisis, indicating a structural pathophysiological relationship.
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Affiliation(s)
- C H B van Niftrik
- Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - M Sebök
- Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - G Muscas
- Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Department of Neurosurgery, Careggi University Hospital, University of Florence, Florence, Italy
| | - S Wegener
- Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Department of Neurology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - A R Luft
- Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Department of Neurology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - C Stippich
- Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Department of Neuroradiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - L Regli
- Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - J Fierstra
- Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Morton AB, Jacobsen NL, Segal SS. Functionalizing biomaterials to promote neurovascular regeneration following skeletal muscle injury. Am J Physiol Cell Physiol 2021; 320:C1099-C1111. [PMID: 33852364 PMCID: PMC8285637 DOI: 10.1152/ajpcell.00501.2020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 03/29/2021] [Accepted: 04/06/2021] [Indexed: 12/18/2022]
Abstract
During embryogenesis, blood vessels and nerves develop with similar branching structure in response to shared signaling pathways guiding network growth. With both systems integral to physiological homeostasis, dual targeting of blood vessels and nerves to promote neurovascular regeneration following injury is an emerging therapeutic approach in biomedical engineering. A limitation to this strategy is that the nature of cross talk between emergent vessels and nerves during regeneration in an adult is poorly understood. Following peripheral nerve transection, intraneural vascular cells infiltrate the site of injury to provide a migratory pathway for mobilized Schwann cells of regenerating axons. As Schwann cells demyelinate, they secrete vascular endothelial growth factor, which promotes angiogenesis. Recent advances point to concomitant restoration of neurovascular architecture and function through simultaneous targeting of growth factors and guidance cues shared by both systems during regeneration. In the context of traumatic injury associated with volumetric muscle loss, we consider the nature of biomaterials used to engineer three-dimensional scaffolds, functionalization of scaffolds with molecular signals that guide and promote neurovascular growth, and seeding scaffolds with progenitor cells. Physiological success is defined by each tissue component of the bioconstruct (nerve, vessel, muscle) becoming integrated with that of the host. Advances in microfabrication, cell culture techniques, and progenitor cell biology hold great promise for engineering bioconstructs able to restore organ function after volumetric muscle loss.
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Affiliation(s)
- Aaron B Morton
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Nicole L Jacobsen
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Steven S Segal
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, Columbia, Missouri
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Franceschina K. Sonographic Evaluation of Peripheral Sciatic Nerve Injury: A Case Study. JOURNAL OF DIAGNOSTIC MEDICAL SONOGRAPHY 2021. [DOI: 10.1177/8756479320988296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Traumatic peripheral nerve injury is not a common finding in the general population but is increasingly being recognized and diagnosed in trauma and emergency medicine settings. Peripheral nerve injury can cause temporary or long-term motor and sensory loss, as well as intense pain and disability, if left untreated. The cause of peripheral nerve injury is diverse and often involves soft tissue damage, fractures, and hemorrhage in cases of traumatic injury. Peripheral nerve injury does not always heal spontaneously and, depending on severity, may warrant surgical intervention and repair. Although electrodiagnosic testing and surgical exploration are considered gold standards for peripheral nerve injury, high-resolution sonographic examination supplemented by clinical findings may be of value. The use of sonography demonstrated utility in determining a strategic management timeline and the efficacy of a surgical intervention.
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Affiliation(s)
- Kirstie Franceschina
- Division of Diagnostic Ultrasound, UCHealth University of Colorado Hospital, Aurora, CO, USA
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50
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Kato H, Okuno T, Isohashi K, Koda T, Shimizu M, Mochizuki H, Nakatsuji Y, Hatazawa J. Astrocyte metabolism in multiple sclerosis investigated by 1-C-11 acetate PET. J Cereb Blood Flow Metab 2021; 41:369-379. [PMID: 32169013 PMCID: PMC7812519 DOI: 10.1177/0271678x20911469] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 01/28/2020] [Accepted: 02/09/2020] [Indexed: 12/12/2022]
Abstract
This study was aimed at evaluating the metabolism of reactive astrocytes in the brains of patients with multiple sclerosis by quantitative 1-C-11 acetate positron emission tomography (PET). Magnetic resonance imaging and 1-C-11 quantitative PET were performed in eight patients with multiple sclerosis and 10 normal control subjects. The efflux rate (k2) of 1-C-11 acetate, which reportedly reflects the metabolic rate of 1-C-11 acetate, was calculated based on the one-tissue compartmental model. Fractional anisotropy was also determined to evaluate the integrity of the neuronal tracts. The values of k2 in the patients with multiple sclerosis were significantly higher than those in the normal control subjects, in both the white matter (p = 0.003) and the gray matter (p = 0.02). In addition, the white matter/gray matter ratio of k2 was significantly higher in the multiple sclerosis patients than in the normal control subjects (p = 0.02). Voxel-based statistical analysis revealed most prominent increase in k2 in the neuronal fiber tracts, as well as decrease in fractional anisotropy in them in the multiple sclerosis patients. The present study clarified that the pathological changes associated with astrocytic reactivation in multiple sclerosis patients could be visualized by quantitative 1-C-11 acetate PET.
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Affiliation(s)
- Hiroki Kato
- Department of Nuclear Medicine and Tracer Kinetics, Osaka University
Graduate School of Medicine, Osaka, Japan
| | - Tatsusada Okuno
- Department of Neurology, Osaka University Graduate School of
Medicine, Osaka, Japan
| | - Kayako Isohashi
- Department of Nuclear Medicine and Tracer Kinetics, Osaka University
Graduate School of Medicine, Osaka, Japan
| | - Toru Koda
- Department of Medical Innovation, Osaka University Hospital
Department of Neurology, Osaka University Graduate School of Medicine, Osaka,
Japan
| | - Mikito Shimizu
- Department of Neurology, Osaka University Graduate School of
Medicine, Osaka, Japan
| | - Hideki Mochizuki
- Department of Neurology, Osaka University Graduate School of
Medicine, Osaka, Japan
| | - Yuji Nakatsuji
- Department of Neurology, Toyama University Hospital, Toyama,
Japan
| | - Jun Hatazawa
- Department of Nuclear Medicine and Tracer Kinetics, Osaka University
Graduate School of Medicine, Osaka, Japan
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