For example, bilateral cerebral infarction can produce atrophy of the intervening corpus callosum due to Wallerian degeneration of the commissural fibers. Polyethylene glycol (PEG) has proven successful in animal models and was applied to human trials. Get Top Tips Tuesday and The Latest Physiopedia updates, The content on or accessible through Physiopedia is for informational purposes only. C and D: 40 hours post crush. If the sprouts cannot reach the tube, for instance because the gap is too wide or scar tissue has formed, surgery can help to guide the sprouts into the tubes. Pierpaoli C, Barnett A, Pajevic S et-al. This testing can further determine Sunderland grade. QUESTION 1. When possible, patients with acute stroke were examined with MR imaging prospectively at the onset of symptoms and then at weekly . Increased distance between hyperechoic lines, Multiple branches involved with loss of fascicular pattern, Proximal end terminal neuroma, homogenous hypoechoic echotexture, Time: very quick to do, faster than EMG or MRI, Dynamic: real time assessment, visualize anatomy with movement and manipulation, Cost: Relatively low cost compared to other modalities, Cannot assess physiological functioning of the nerve, Prognosis: cannot distinguish between neurotmetic and neuropraxic lesions. Muscle and tendon transfers can lead to adhesive scarring in the antagonist muscle and prevent proper tendon function. Traumatic injury to peripheral nerves results in the loss of neural functions. 2004;46 (3): 183-8. Many rare diseases have limited information. After the 21st day, acute nerve degeneration will show on the electromyograph. During injury, nerves become more hyperintense on T2 and, given the chronicity, muscle atrophy may be present and localized edema canbeseen. [44] This collapse in NAD+ levels was later shown to be due to SARM1's TIR domain having intrinsic NAD+ cleavage activity. [24] Macrophages also stimulate Schwann cells and fibroblasts to produce NGF via macrophage-derived interleukin-1. Wallerian degeneration (WD) is the process of progressive demyelination and disintegration of the distal axonal segment following the transection of the axon or damage to the neuron. De simone T, Regna-gladin C, Carriero MR et-al. Soluble factors produced by Schwann cells and injured axons activate resident macrophages and lead to recruitment of hematogenous macrophages. Various possibilities have been studied to improve/accelerate nerve repair/regeneration via neuronal-death reduction and axonal-growth enhancement. Wallerian degeneration is an active process of degeneration that results when a nerve fiber is cut or crushed and the part of the axon distal to the injury (which in most cases is farther from the neuron's cell body) degenerates. Prior to degeneration, the distal section of the axon tends to remain electrically excitable. This occurs by the 7th day when macrophages are signaled by the Schwann cells to clean up axonal and myelin debris. On the contrary, axonotmesis and neurotmesis take longer to recover and may not recover as well, or at all. Gaudet AD, PopovichPG &Ramer MS. Wallerian degeneration: Gaining perspective on inflammatory events after peripheral nerve injury.Journal of Neuroinflammation.2011 Available from. Another key aspect is the change in permeability of the blood-tissue barrier in the two systems. If surgery is warranted to the nerve injury, the type of surgery could dictate healing and outcomes. (2010) Polish journal of radiology. The seminal discovery of the slow Wallerian degeneration mice (Wld) in which transected axons do not degenerate but survive and . 4.7-T diffusion tensor imaging of acute traumatic peripheral nerve injury. Neuregulins are believed to be responsible for the rapid activation. Granular disintegration of the axonal cytoskeleton and inner organelles occurs after axolemma degradation. However, only complement has shown to help in myelin debris phagocytosis.[14]. Radiology. Extensive axonotmesis cannot be differentiated initially from neurotmesis by either clinical or electrodiagnostic examination. Another feature that results eventually is Glial scar formation. 16 (1): 125-33. Sunderland grades 1-3 are treated with conservative measures while grades 4-5 usually require surgical repair. The innate and adaptive immune systems are believed to be critical for facilitating the clearance of myelin and axonal debris during this process. Read More . What will the . Axonal degeneration is followed by degradation of the myelin sheath and infiltration by macrophages. Murinson et al. Regeneration is efficient in the PNS, with near complete recovery in case of lesions that occur close to the distal nerve terminal. If any of your symptoms worsen or change after your physical exam, it is important to follow-up with your health care provider. The degenerating nerve also produce macrophage chemotactic molecules. In addition, however, there is a diffuse inflammatory process in the "normal" white matter of MS patients, which by itself is associated with blood . https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-8-110, "An 85-kb tandem triplication in the slow Wallerian degeneration (Wlds) mouse", https://www.youtube.com/watch?v=kbzYML05Vac, https://www.https://www.youtube.com/watch?v=P02ea4jf50g&t=192s, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315870/, https://www.physio-pedia.com/index.php?title=Wallerian_Degeneration&oldid=274325, Reduced or loss of function in associated structures to damaged nerves, Gradual onset of numbness, prickling or tingling in feet or hands, which can spread upward into legs and arms, Sharp, jabbing, throbbing, freezing, or burning pain. Peripheral nerve reconstruction after injury: a review of clinical and experimental therapies. Some of the agents include erythropoietin, tacrolimus, acetyl-L-carnitine, N-acetylcysteine, testosterone, chondroitinase ABC, dimethylsulfoxide, transthyretin (pre-albumin), ibuprofen, melatonin, and polyethylene glycol. which results in wallerian degeneration. Surgical repair is further classified based on the size of the nerve gap and include primary repair, conduits, allografts, and autografts. Schwann cells respond to loss of axons by extrusion of their myelin sheaths, downregulation of myelin genes, dedifferentiation and proliferation. Promising new developments are under investigation that may help to suppress symptoms and restore function. The axons are bundled together into groups calledfascicles, and each fascicle is wrapped in a layer of connective tissue called theperineurium. Wallerian degeneration in the corpus callosum. 2001; Rotshenker 2007)] could all be factors affecting the visual white matter depending on . Available from, The Young Orthopod. Solved QUESTION 1 Carpal tunnel and tarsal tunnel syndrome - Chegg Two mechanisms of nerve recovery resulting in re-innervation of end-organs occur simultaneously: Collateral branching/sprouting of intact axons, Primary mechanism when 20-30% of axons injured, Starts within 4 days of injury and proceeds for 3-6 months, Primary method when greater than 90% of axons injured. Axonal injury in multiple sclerosis | Journal of Neurology While Alzheimer's disease (AD) is the most common neurodegenerative disease that causes it, more than 50 Frontotemporal lobar dementia and amyotrophic lateral sclerosis Diffusionweighted imaging (DWI) and corresponding apparent diffusion coefficient (ADC) map in a patient with a large parietooccipital lobar intracerebral hemorrhage, showing reduced diffusion (bright on DWI and dark on ADC) in the splenium of the corpus callosum from Wallerian degeneration. But opting out of some of these cookies may have an effect on your browsing experience. Possible effects of this late onset are weaker regenerative abilities in the mice. [7] Within 4 days of the injury, the distal end of the portion of the nerve fiber proximal to the lesion sends out sprouts towards those tubes and these sprouts are attracted by growth factors produced by Schwann cells in the tubes. [48][49] One explanation for the protective effect of the WldS mutation is that the NMNAT1 region, which is normally localized to the soma, substitutes for the labile survival factor NMNAT2 to prevent SARM1 activation when the N-terminal Ube4 region of the WldS protein localizes it to the axon. Purpose of review: Diffuse or traumatic axonal injury is one of the principal pathologies encountered in traumatic brain injury (TBI) and the resulting axonal loss, disconnection, and brain atrophy contribute significantly to clinical morbidity and disability. Anterograde volume loss after stroke can occur through either "wallerian" degeneration of the lesioned neurons or transsynaptic degeneration. Given that proteasome in- portant for the DNA damage response, and Axonal degeneration (termed Wallerian hibitors block Wallerian degeneration both degeneration) often precedes the death of in vitro and in vivo (5), the Ufd2a protein neuronal cell bodies in neurodegenerative fragment (a component of the ubiquitin A. Bedalov is in the Clinical . hb```aB =_rA The type of surgery can be guided by the size of the gap of injury: Autologous graft to provide a conduit for axonal regrowth. Carpal tunnel and . Severity is classified by pathologic findings: neurapraxia, axonotmesis, and neurotmesis, also known as Seddon Classification. Wallerian degeneration is the process of antegrade degeneration of the axons and their accompanying myelin sheaths following proximal axonal or neuronal cell body lesions. Axon degeneration is a prominent early feature of most neurodegenerative disorders and can also be induced directly by nerve injury in a process known as Wallerian degeneration. Wallerian degeneration (the clearing process of the distal stump), axonal regeneration, and end-organ reinnervation. [11] These signaling molecules together cause an influx of macrophages, which peaks during the third week after injury. Therefore, most peripheral nerve injuries are initially are managed conservatively, with nerve function evaluation at 3 weeks via nerve conduction study and electromyography (NCS/EMG). [36] More recent work, however, raises doubt that either NMNAT1 or NAD+ can substitute for the full length Wlds gene. . The typical example is Wallerian degeneration (WD), which results from traumatic or ischemic injuries that disconnect the neuronal cell body from the distal segment of the axon. Us20220072019a1 Inhibitors of Sarm1 in Combination With Nad+ or A Nad+ Ultrasound (US) can accurately diagnose various nerve injuries, especially superficial nerves, but it can be limited by anatomy, body habitus, edema, and architecture distortions with deeper structures. Epidemiology. It is named after the English neurophysiologist Augustis Volney Waller (1816-1870), who described the process in 1850 6. Check for errors and try again. Differentiating phagocytic microglia can be accomplished by testing for expression of Major histocompatibility complex (MHC) class I and II during wallerian degeneration. These cookies will be stored in your browser only with your consent. Similarly . {"url":"/signup-modal-props.json?lang=us"}, St-Amant M, Smith D, Baba Y, et al. In neurotmesis (Sunderland grade 5), the axon and all surrounding connective tissue (endoneurium, perineurium, and epineurium) are damaged (i.e., transected nerve). The study of disease molecular components is known as molecular pathology. The most commonly observed pattern is an injury to the precentral gyrus (such as may be seen in an MCA infarct) with resultant degeneration of the corticospinal tracts. Peripheral nerve injury results in orchestrated changes similar to the Wallerian degeneration leading to structural and functional alterations which affect the whole peripheral nervous system including peripheral nerve endings, afferent fibers, dorsal root ganglion (DRG) and also central afferent terminals in the spinal cord (Austin et al., 2012). Wallerian Degeneration (Loss of the Nerve Axon with an Intact Myelin Sheath) In this type of motor nerve injury, the long body of the nerve (the axon) is injured but the myelin sheath (the insulation) remains intact. [41][42], SARM1 catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) from NAD+ to ADP-ribose. The Wlds mutation is an autosomal-dominant mutation occurring in the mouse chromosome 4. 1173185. Schwann cell divisions were approximately 3 days after injury. Sequential electrodiagnostic examinations may help predict recovery: As noted above, reinnervation by collaterals may result in polyphasic MUAPs and/or satellite potentials, while the slower axonal re-growth will eventually result in larger amplitude, longer duration potentials. wherein a chronic central nervous system disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sc Axonal degeneration occurs either as a primarily axonal process or as a bystander-type axonal degeneration, associated with . [11], These findings have suggested that the delay in Wallerian degeneration in CNS in comparison to PNS is caused not due to a delay in axonal degeneration, but rather is due to the difference in clearance rates of myelin in CNS and PNS. Current understanding of the process has been possible via experimentation on the Wlds strain of mice. These require further exploration and clinical trials: The current standards of care for peripheral nerve injury is based on serial examinations and/or electrodiagnostics. This website uses cookies to improve your experience while you navigate through the website. In addition, cost-effective approaches to following progress to recovery are needed. [8] After separation, dystrophic bulb structures form at both terminals and the transected membranes are sealed. hbbd``b` $[A>`A ">`W = $>f`bdH!@ During Wallerian degeneration, Schwann cells both phagocytose the axonal and myelin debris and help regenerate myelin. Nerve Regeneration. Schwann cells and endoneural fibroblasts in PNS. Affected axons may . [31] This in turn activates SIRT1-dependent process within the nucleus, causing changes in gene transcription. Wallerian degeneration as a therapeutic target in traumatic brain In the first weeks to months, re-innervation by collaterals may result in polyphasic MUAPs and/or satellite potentials, while the slower axonal re-growth will eventually result in larger amplitude, longer duration potentials. These. is one of the most devastating symptoms of neurologic disease. 385 0 obj <> endobj During their proliferation phase, Schwann cells begin to form a line of cells called Bands of Bungner within the basal laminar tube. Transient detection of early wallerian degeneration on diffusion-weighted MRI after an acute cerebrovascular accident. The possible source of error that could result from this is possible mismatching of the target cells as discussed earlier. For axonotmesis and neurotmesis, the EMG findings listed are distal to the lesion in the relevant nerve territory. . Wallerian degeneration is a process of antegrade neural disintegration that develops after injury to the proximal axon or cell body. Wallerian Degeneration of the Pontocerebellar Fibers Disease pathology is the study of the symptoms and signs of diseases and how they change over time. A and B: 37 hours post cut. Peripheral nerve injuries - Knowledge @ AMBOSS 8-13 The cerebral peduncle is ideal for assessing postinfarction wallerian degeneration . Pathological Procedures: Histopathological And Immunohistochemical Axonal degeneration may be necessary pathophysiological process for serum CK elevation given that not just AMAN patients but also AIDP patients . Schwann cell activation should therefore be delayed, as they would not detect axonal degradation signals from ErbB2 receptors. G and H: 44 hours post crush. This website uses cookies to improve your experience. Subclavian steal syndrome is the medical term for a group of signs and symptoms that indicate retrograde blood flow in an artery. After the 21st day, acute nerve degeneration will show on the electromyograph. Prevention of vincristine-induced peripheral neuropathy by genetic Medical & Exercise Physiology School.Wallerian degeneration/ regeneration process of nerve fiber/axon cut and progressive response. [45] Activation of SARM1 is sufficient to collapse NAD+ levels and initiate the Wallerian degeneration pathway.[44]. Wallerian degeneration - About the Disease - Genetic and Rare Diseases 26. Therefore, unlike Schwann cells, oligodendrocytes fail to clean up the myelin sheaths and their debris. R. Soc. In addition, recovery of injury is highly dependent on the severity of injury. 1989;172 (1): 179-82. London 1850, 140:42329, 7. Deficiency of adaptive immunity does not interfere with Wallerian Philos. They activate ErbB2 receptors in the Schwann cell microvilli, which results in the activation of the mitogen-activated protein kinase (MAPK). (1995) AJNR. A Regeneration of the nerve by slow axonal transport B A positive Phalen sign C Wallerian degeneration proximal to the compression. It is noteworthy that these TAD-like lesions do not come with classic Wallerian-type axonal degeneration and evolve through a dose limiting manner [12,13,14]. Although most injury responses include a calcium influx signaling to promote resealing of severed parts, axonal injuries initially lead to acute axonal degeneration (AAD), which is rapid separation of the proximal (the part nearer the cell body) and distal ends within 30 minutes of injury. The recruitment of macrophages helps improve the clearing rate of myelin debris. [37] These authors demonstrated by both in vitro and in vivo methods that the protective effect of overexpression of NMNAT1 or the addition of NAD+ did not protect axons from degeneration. The Present and Future for Peripheral Nerve Regeneration. An example of a peripheral nerve structure, Table 1 Classification of Peripheral Nerve Injury, A. Schwann cells emit growth factors that attract new axonal sprouts growing from the proximal stump after complete degeneration of the injured distal stump. It occurs between 7 to 21 days after the lesion occurs. The cell bodies of the motor nerves are located in the brainstem and ventral horn of the spinal cord while those of the sensory nerves are located outside of the spinal cord in the dorsal root ganglia (Fig 1)1. The 3 major groups found in serum include complement, pentraxins, and antibodies. Peripheral nerve injury: principles for repair and regeneration. It may result following neuronal loss due to cerebral infarction, trauma, necrosis, focal demyelination, or haemorrhage . About 20% of patients end up with respiratory failure. [47] Other pro-degeneration signaling pathways, such as the MAP kinase pathway, have been linked to SARM1 activation. or clinical procedures, such as a hearing test. At the time the article was created Maxime St-Amant had no recorded disclosures. Neurology | Nerve Injury & Repair: Wallerian Degeneration However, later studies showed that NMNAT1 is protective when combined with an axonal targeting peptide, suggesting that the key to the protection provided by WldS was the combination of NMNAT1's activity and the axonal localization provided by the N-terminal domain of the chimeric protein. . The prolonged presence of myelin debris in CNS could possibly hinder the regeneration. Griffin M, Malahias M, Hindocha S, Khan WS. The gene was first identified in a Drosophila melanogaster mutagenesis screen, and subsequently knockouts of its homologue in mice showed robust protection of transected axons comparable to that of WldS. [25] Other neurotrophic molecules produced by Schwann cells and fibroblasts together include brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, ciliary neurotrophic factor, leukemia inhibitory factor, insulin-like growth factor, and fibroblast growth factor. This will produce a situation called Wallerian Degeneration. One study found that during a surgical repair of a sharp, complete resection, the application of PEG for 2 minutes after surgical connection of the injured ends, helps to decrease inappropriate calcium-mediated vesicle formation, promote fusion, enhance axonal continuity with nerve healing, and improve sensory recovery, based on static two-point discrimination. soft tissue. [34][35], The mutation causes no harm to the mouse. David Haustein, MD; Mariko Kubinec, MD; Douglas Stevens, MD; and Clinton Johnson, DO. However, Wallerian degeneration is thought of as a rare or a late finding in MS. Methods: Studies showing a classic Wallerian degeneration pattern in the corticospinal tract were selected from a review of MR studies from patients enrolled in a longitudinal treatment trial. At first, it was suspected that the Wlds mutation slows down the macrophage infiltration, but recent studies suggest that the mutation protects axons rather than slowing down the macrophages. Thus, secondary "Wallerian" degeneration is an important element, underlying diffuse abnormalities and axonal loss in the so called normal white matter, typically found in MS brains. Neuroradiology. neuropraxia) recover in shorter amount of time and to a better degree. endstream endobj 386 0 obj <>/Metadata 13 0 R/PageLayout/OneColumn/Pages 383 0 R/StructTreeRoot 17 0 R/Type/Catalog>> endobj 387 0 obj <>/Font<>>>/Rotate 0/StructParents 0/Type/Page>> endobj 388 0 obj <>stream When the regenerating axon reaches the end organ, the axon matures and becomes myelinated. If the axons fail to cross over the injury site, the distal segment is permanently denervated and the axonal growth from the proximal segment forms a neuroma. The mutation occurred first in mice in Harlan-Olac, a laboratory producing animals the United Kingdom. He then observed the distal nerves from the site of injury, which were separated from their cell bodies in the brain stem. As in axonotmesis, if there is any re-innervation by collaterals, EMG may reveal polyphasic MUAPs and/or satellite potentials, while the slower axonal re-growth will eventually result in larger amplitude, longer duration potentials. PDF EMG Cheat Sheet It may result following neuronal loss due to cerebral infarction, trauma, necrosis, focal demyelination, or hemorrhage . The distal nerve, particularly . The macrophages, accompanied by Schwann cells, serve to clear the debris from the degeneration.[5][6]. [10] Degeneration follows with swelling of the axolemma, and eventually the formation of bead-like axonal spheroids. Symptoms include progressive weakness and muscle wasting of the legs and arms. Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia AS, McNamara JO, White LE. PDF e uroinfectio ournal of euroinfectious Diseases The dynamic signal intensity changes at magnetic resonance (MR) imaging in active and chronic wallerian degeneration in the corticospinal tract were evaluated. Peripheral neurological recovery and regeneration. (PDF) Wallerian Degeneration - researchgate.net [32][33] The protection provided by the WldS protein is intrinsic to the neurons and not surrounding support cells, and is only locally protective of the axon, indicating an intracellular pathway is responsible for mediating Wallerian degeneration. Wallerian degeneration - Wikipedia 2. Symptoms: This section is currently in development. Temperature Modulation Reveals Three Distinct Stages of Wallerian An assessment of fatigability following nerve transfer to reinnervate elbow flexor muscles. Neurapraxia is a disorder of the peripheral nervous system in which there is a temporary loss of motor and sensory function due to blockage of nerve conduction, usually lasting an average of six to eight weeks before full recovery. Question: QUESTION 1 Carpal tunnel and tarsal tunnel syndrome cause nerve degeneration resulting in specific symptoms and changes in the nerves. Reinnervated fibers develop an increase in type II motor fibers (fast twitch, anaerobic fibers). Affiliated tissues include spinal cord, dorsal root ganglion and brain, and related phenotypes are Increased shRNA abundance (Z-score > 2) and nervous system. This occurs in less than a day and allows for nerve renervation and regeneration. Wallerian Degeneration of the Corticofugal Tracts in Chronic Stroke: A Those microglia that do transform, clear out the debris effectively. NCS: In the first few days after the injury, there will be reduced conduction across the lesion but conduction may be normal above and below the lesion until Wallerian degeneration occurs. About the Disease ; Getting a Diagnosis ; . Wallerian degeneration | Radiology Reference Article | Radiopaedia.org A novel therapy to promote axonal fusion in human digital nerves. [6] The process by which the axonal protection is achieved is poorly understood. Left column is proximal to the injury, right is distal. Sensory symptoms often precede motor weakness. Out of these cookies, the cookies that are categorized as necessary are stored on your browser as they are essential for the working of basic functionalities of the website. Schwann cells continue to clear up the myelin debris by degrading their own myelin, phagocytose extracellular myelin and attract macrophages to myelin debris for further phagocytosis. Diffusiontensorimaging(DTI), a type of MR, can quantify axon density and myelin thickness. Needle EMG: Effective immediately, there will be decreased recruitment in partial lesions and unobtainable MUAPs/absent recruitment in complete lesions. 75 (4): 38-43. Studies indicate that regeneration may be impaired in WldS mice, but this is likely a result of the environment being unfavorable for regeneration due to the continued existence of the undegenerated distal fiber, whereas normally debris is cleared, making way for new growth. Oligodendrocytes fail to recruit macrophages for debris removal. Repairs with grafts can sometimes result in poor functional outcomes as a consequence of fibrosis and endplate degeneration. ADVERTISEMENT: Supporters see fewer/no ads. Paralysis and sensory loss develop acutely, but nerve conduction of the distal segment only remains intact until the distal segment is consumed by Wallerian degeneration. Official Ninja Nerd Website: https://ninjanerd.orgNinja Nerds!In this lecture Professor Zach Murphy will be discussing nerve injury along with wallerian dege. Site: if the muscle is very deep or limited by body habitus,MRI could be a better option than EMG. Time: provider may be able to have study done sooner if a timely EMG isdifficultto obtain. AJNR Am J Neuroradiol. The rate of degradation is dependent on the type of injury and is also slower in the CNS than in the PNS. The most common symptoms of a pinched nerve include neck pain that travels down the arms and shoulders, difficulty lifting things, headache, and muscle weakness and numbness or tingling in fingers or hands. [2] Primary culture studies suggest that a failure to deliver sufficient quantities of the essential axonal protein NMNAT2 is a key initiating event. Furthermore, this microdamage alters only the static phase firing sensory component of the stretch reflex and leaves the dynamic sensory encoding basically unharmed . Unable to process the form. Poststroke Cerebral Peduncular Atrophy Correlates with a Measure of [19] The rate of clearance is very slow among microglia in comparison to macrophages. Patients and doctors enter symptoms, answer questions, and find a list of matching causes - sorted by probability. For the treatment of traumatic nerve injuries, future research in pharmacologic interventions and gene therapy needs to be expanded to human subjects. An intronic GGGGCC repeat expansion in c9orf72 gene has been identified as the most common genetic cause of frontotemporal lobar dementia (FTLD), amyotrophic lateral sclerosis (ALS) and FTLD-ALS. PEG helps fuse cells, develop desired cell lines, remove water at the injured lipid bilayer, and increase the fusion of axolemmal ends. Open injuries with complete nerve transection are repaired based on the laceration type. Trans. Read more, Physiopedia 2023 | Physiopedia is a registered charity in the UK, no. Kuhn MJ, Mikulis DJ, Ayoub DM et-al. Mice belonging to the strain C57BL/Wlds have delayed Wallerian degeneration,[28] and, thus, allow for the study of the roles of various cell types and the underlying cellular and molecular processes. [31], Although the protein created localizes within the nucleus and is barely detectable in axons, studies suggest that its protective effect is due to its presence in axonal and terminal compartments.