Secondary Neurodegeneration: A General Approach to Axonal and Transaxonal Degeneration

Neurographics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 111-126
Author(s):  
F.B. Assunção ◽  
T.L.P.D. Scoppetta ◽  
B.S. Yonekura Inada ◽  
L.D.A. Martins ◽  
E.O Narvaez ◽  
...  
Keyword(s):  
Wallerian Degeneration ◽  
Single Neuron ◽  
Axonal Degeneration ◽  
Corticospinal Tract ◽  
Neuronal Degeneration ◽  
Imaging Modalities ◽  
Nigrostriatal Pathway ◽  
Common Pathway ◽  
Neurologic Diseases ◽  
Nerve Tracts

CNS WM tracts are mainly composed of axons, and when these structures undergo apoptosis or lose their integrity, neurodegeneration may occur. Secondary neuronal degeneration can be classified as axonal degeneration and involves only the first neuron in a pathway (Wallerian degeneration of the corticospinal tract being its prototype) or be classified as transaxonal degeneration and involve more than a single neuron in a common pathway, usually a closed neuronal circuit, in specific tracts, such as the dentate-rubro-olivary tract, tracts of the limbic system, corticopontocerebellar tract, cranial nerve tracts, and nigrostriatal pathway. This study aimed to review the anatomy of the main CNS tracts susceptible to secondary neuronal degeneration and to illustrate, through different imaging modalities, the findings associated with this poorly explored and understood process involved in the pathophysiologic substrate of numerous neurologic diseases.Learning Objective: Recognize the anatomy of the main CNS tracts susceptible to secondary neuronal degeneration and identify its main imaging findings in different imaging modalities.

scholarly journals Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Matthew A. White ◽  
Ziqiang Lin ◽  
Eugene Kim ◽  
Christopher M. Henstridge ◽  
Emiliano Pena Altamira ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Mouse Model ◽  
Motor Neuron ◽  
Transgenic Mouse ◽  
Entorhinal Cortex ◽  
Wallerian Degeneration ◽  
Axonal Degeneration ◽  
Primary Motor Cortex ◽  
Neuronal Degeneration ◽  
Age Related

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition that primarily affects the motor system and shares many features with frontotemporal dementia (FTD). Evidence suggests that ALS is a ‘dying-back’ disease, with peripheral denervation and axonal degeneration occurring before loss of motor neuron cell bodies. Distal to a nerve injury, a similar pattern of axonal degeneration can be seen, which is mediated by an active axon destruction mechanism called Wallerian degeneration. Sterile alpha and TIR motif-containing 1 (Sarm1) is a key gene in the Wallerian pathway and its deletion provides long-term protection against both Wallerian degeneration and Wallerian-like, non-injury induced axonopathy, a retrograde degenerative process that occurs in many neurodegenerative diseases where axonal transport is impaired. Here, we explored whether Sarm1 signalling could be a therapeutic target for ALS by deleting Sarm1 from a mouse model of ALS-FTD, a TDP-43Q331K, YFP-H double transgenic mouse. Sarm1 deletion attenuated motor axon degeneration and neuromuscular junction denervation. Motor neuron cell bodies were also significantly protected. Deletion of Sarm1 also attenuated loss of layer V pyramidal neuronal dendritic spines in the primary motor cortex. Structural MRI identified the entorhinal cortex as the most significantly atrophic region, and histological studies confirmed a greater loss of neurons in the entorhinal cortex than in the motor cortex, suggesting a prominent FTD-like pattern of neurodegeneration in this transgenic mouse model. Despite the reduction in neuronal degeneration, Sarm1 deletion did not attenuate age-related behavioural deficits caused by TDP-43Q331K. However, Sarm1 deletion was associated with a significant increase in the viability of male TDP-43Q331K mice, suggesting a detrimental role of Wallerian-like pathways in the earliest stages of TDP-43Q331K-mediated neurodegeneration. Collectively, these results indicate that anti-SARM1 strategies have therapeutic potential in ALS-FTD.

scholarly journals Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Barakat Alrashdi ◽  
Bassel Dawod ◽  
Andrea Schampel ◽  
Sabine Tacke ◽  
Stefanie Kuerten ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Retinal Ganglion Cells ◽  
Axonal Degeneration ◽  
Ganglion Cells ◽  
Neuronal Degeneration ◽  
Retinal Ganglion ◽  
Autoimmune Encephalomyelitis ◽  
Aav Vector ◽  
Α Subunit

Abstract Background In multiple sclerosis (MS) and in the experimental autoimmune encephalomyelitis (EAE) model of MS, the Nav1.6 voltage-gated sodium (Nav) channel isoform has been implicated as a primary contributor to axonal degeneration. Following demyelination Nav1.6, which is normally co-localized with the Na+/Ca2+ exchanger (NCX) at the nodes of Ranvier, associates with β-APP, a marker of neural injury. The persistent influx of sodium through Nav1.6 is believed to reverse the function of NCX, resulting in an increased influx of damaging Ca2+ ions. However, direct evidence for the role of Nav1.6 in axonal degeneration is lacking. Methods In mice floxed for Scn8a, the gene that encodes the α subunit of Nav1.6, subjected to EAE we examined the effect of eliminating Nav1.6 from retinal ganglion cells (RGC) in one eye using an AAV vector harboring Cre and GFP, while using the contralateral either injected with AAV vector harboring GFP alone or non-targeted eye as control. Results In retinas, the expression of Rbpms, a marker for retinal ganglion cells, was found to be inversely correlated to the expression of Scn8a. Furthermore, the gene expression of the pro-inflammatory cytokines Il6 (IL-6) and Ifng (IFN-γ), and of the reactive gliosis marker Gfap (GFAP) were found to be reduced in targeted retinas. Optic nerves from targeted eyes were shown to have reduced macrophage infiltration and improved axonal health. Conclusion Taken together, our results are consistent with Nav1.6 promoting inflammation and contributing to axonal degeneration following demyelination.

scholarly journals Hypertrophic olivary degeneration concomitant with bilateral middle cerebellar peduncles Wallerian degeneration following unilateral pontine infarction

BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Bing Bao ◽  
Xiangbin Wu ◽  
Zhongbin Xia ◽  
Yaoyao Shen
Keyword(s):  
Wallerian Degeneration ◽  
Corticospinal Tract ◽  
Brain Magnetic Resonance Imaging ◽  
Acute Onset ◽  
Case Presentation ◽  
Hypertrophic Olivary Degeneration ◽  
Pontine Infarction ◽  
Cerebellar Peduncles ◽  
Magnetic Resonance Imaging Mri

Abstract Background Wallerian degeneration (WD) can occur in different projecting systems, such as corticospinal tract, dentate-rubro-olivary pathway, and corticopontocerebellar tract. However, the co-occurrence of hypertrophic olivary degeneration (HOD) and middle cerebellar peduncles (MCPs) degeneration secondary to unilateral pontine infarction in a single patient is extremely rare. Case presentation A 71-year-old man presented with acute onset of dizzness, slurred speech, and right-sided weakness. On the next day, his previous neurologic deficits deteriorated. Brain magnetic resonance imaging (MRI) revealed acute ischemic stroke of the left pons. After treatment with thrombolysis, antiplatelets, and rehabilitation training, his speaking and motor function improved moderately. At the 3-month follow-up, the MRI showed hyperintensity in the left medulla oblongata and bilateral MCPs on T2-weighted and FLAIR images, suggesting HOD as well as MCPs degeneration. Conclusions It is of great importance for us to know the anatomic knowledge of dentate-rubro-olivary and corticopontocerebellar pathways.

scholarly journals Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Aysel Cetinkaya-Fisgin ◽  
Xinghua Luan ◽  
Nicole Reed ◽  
Ye Eun Jeong ◽  
Byoung Chol Oh ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Side Effects ◽  
Cancer Cells ◽  
Wallerian Degeneration ◽  
Axonal Degeneration ◽  
Adduct Formation ◽  
Calpain Activation ◽  
Chemotherapy Agent ◽  
Distal Axonal Degeneration ◽  
Calpain Inhibitors

AbstractCisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in cancer cells. Furthermore, we show that neurotoxicity of cisplatin requires activation of Sarm1, a key regulator of Wallerian degeneration, as mice lacking the Sarm1 gene do not develop peripheral neuropathy as evaluated by both behavioral or pathological measures. These findings indicate that Sarm1 and/or specific calpain inhibitors could be developed to prevent cisplatin induced peripheral neuropathy.

scholarly journals Brain-on-a-chip microsystem for investigating traumatic brain injury: Axon diameter and mitochondrial membrane changes play a significant role in axonal response to strain injuries

TECHNOLOGY ◽  
2014 ◽  
Vol 02 (02) ◽  
pp. 106-117 ◽  
Author(s):  
Jean-Pierre Dollé ◽  
Barclay Morrison ◽  
Rene S. Schloss ◽  
Martin L. Yarmush
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Significant Role ◽  
Mitochondrial Membrane ◽  
Axonal Degeneration ◽  
Neuronal Degeneration ◽  
Diffuse Axonal Injury ◽  
Injury Threshold ◽  
Chip Technology ◽  
Axonal Diameter

Diffuse axonal injury (DAI) is a devastating consequence of traumatic brain injury, resulting in significant axon and neuronal degeneration. Currently, therapeutic options are limited. Using our brain-on-a-chip device, we evaluated axonal responses to DAI. We observed that axonal diameter plays a significant role in response to strain injury, which correlated to delayed elasticity and inversely correlated to axonal beading and axonal degeneration. When changes in mitochondrial membrane potential (MMP) were monitored an applied strain injury threshold was noted, below which delayed hyperpolarization was observed and above which immediate depolarization occurred. When the NHE-1 inhibitor EIPA was administered before injury, inhibition in both hyperpolarization and depolarization occurred along with axonal degeneration. Therefore, axonal diameter plays a significant role in strain injury and our brain-on-a-chip technology can be used both to understand the biochemical consequences of DAI and screen for potential therapeutic agents.

scholarly journals Oxidative stress–dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration

2015 ◽  
Vol 211 (4) ◽  
pp. 881-896 ◽  
Author(s):  
Shuji Wakatsuki ◽  
Akiko Furuno ◽  
Makiko Ohshima ◽  
Toshiyuki Araki
Keyword(s):  
Oxidative Stress ◽  
Ubiquitin Ligase ◽  
Wallerian Degeneration ◽  
Neuronal Apoptosis ◽  
Axonal Degeneration ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Growth Factor Receptor ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Ligase Activity ◽  
Stress Dependent

Oxidative stress is a well-known inducer of neuronal apoptosis and axonal degeneration. We previously showed that the E3 ubiquitin ligase ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B activation. We now demonstrate that oxidative stress serves as an activator of the ubiquitin ligase activity of ZNRF1 by inducing epidermal growth factor receptor (EGFR)–mediated phosphorylation at the 103rd tyrosine residue and that the up-regulation of ZNRF1 activity by oxidative stress leads to neuronal apoptosis and Wallerian degeneration. We also show that nicotinamide adenine dinucleotide phosphate–reduced oxidase activity is required for the EGFR-dependent phosphorylation-induced activation of ZNRF1 and resultant AKT degradation via the ubiquitin proteasome system to induce Wallerian degeneration. These results indicate the pathophysiological significance of the EGFR–ZNRF1 pathway induced by oxidative stress in the regulation of neuronal apoptosis and Wallerian degeneration. A deeper understanding of the regulatory mechanism for ZNRF1 catalytic activity via phosphorylation will provide a potential therapeutic avenue for neurodegeneration.

scholarly journals Myelin sheath survival after guanethidine-induced axonal degeneration.

1992 ◽  
Vol 116 (2) ◽  
pp. 395-403 ◽  
Author(s):  
G J Kidd ◽  
J W Heath ◽  
B D Trapp ◽  
P R Dunkley
Keyword(s):  
Schwann Cells ◽  
Superior Cervical Ganglion ◽  
Myelin Sheath ◽  
Axonal Regeneration ◽  
Wallerian Degeneration ◽  
Axonal Degeneration ◽  
Serial Sections ◽  
Myelin Sheaths ◽  
Cervical Ganglion ◽  
Contrast Analysis

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

scholarly journals Wallerian degeneration in cervical spinal cord tracts is commonly seen in routine T2-weighted MRI after traumatic spinal cord injury and is associated with impairment in a retrospective study

2020 ◽  
Author(s):  
Tim Fischer ◽  
Christoph Stern ◽  
Patrick Freund ◽  
Martin Schubert ◽  
Reto Sutter
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Wallerian Degeneration ◽  
Evoked Potential ◽  
Corticospinal Tract ◽  
Cervical Spinal Cord ◽  
Dorsal Column ◽  
Traumatic Spinal Cord Injury ◽  
Spinothalamic Tract ◽  
Cord Injury

Abstract Objectives Wallerian degeneration (WD) is a well-known process after nerve injury. In this study, occurrence of remote intramedullary signal changes, consistent with WD, and its correlation with clinical and neurophysiological impairment were assessed after traumatic spinal cord injury (tSCI). Methods In 35 patients with tSCI, WD was evaluated by two radiologists on T2-weighted images of serial routine MRI examinations of the cervical spine. Dorsal column (DC), lateral corticospinal tract (CS), and lateral spinothalamic tract (ST) were the analyzed anatomical regions. Impairment scoring according to the American Spinal Injury Association Impairment Scale (AIS, A–D) as well as a scoring system (0–4 points) for motor evoked potential (MEP) and sensory evoked potential (SEP) was included. Mann-Whitney U test was used to test for differences. Results WD in the DC occurred in 71.4% (n = 25), in the CS in 57.1% (n = 20), and in 37.1% (n = 13) in the ST. With WD present, AIS grades were worse for all tracts. DC: median AIS B vs D, p < 0.001; CS: B vs D, p = 0.016; and ST: B vs D, p = 0.015. More pathological MEP scores correlated with WD in the DC (median score 0 vs 3, p < 0.001) and in the CS (0 vs 2, p = 0.032). SEP scores were lower with WD in the DC only (1 vs 2, p = 0.031). Conclusions WD can be detected on T2-weighted scans in the majority of cervical spinal cord injury patients and should be considered as a direct effect of the trauma. When observed, it is associated with higher degree of impairment. Key Points • Wallerian degeneration is commonly seen in routine MRI after traumatic spinal cord injury. • Wallerian degeneration is visible in the anatomical regions of the dorsal column, the lateral corticospinal tract, and the lateral spinothalamic tract. • Presence of Wallerian degeneration is associated with higher degree of impairment.

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