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The Journal of Clinical Investigation Jun 2023Neurons are markedly compartmentalized, which makes them reliant on axonal transport to maintain their health. Axonal transport is important for anterograde delivery of... (Review)
Review
Neurons are markedly compartmentalized, which makes them reliant on axonal transport to maintain their health. Axonal transport is important for anterograde delivery of newly synthesized macromolecules and organelles from the cell body to the synapse and for the retrograde delivery of signaling endosomes and autophagosomes for degradation. Dysregulation of axonal transport occurs early in neurodegenerative diseases and plays a key role in axonal degeneration. Here, we provide an overview of mechanisms for regulation of axonal transport; discuss how these mechanisms are disrupted in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, hereditary spastic paraplegia, amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease; and discuss therapeutic approaches targeting axonal transport.
Topics: Humans; Axonal Transport; Neurodegenerative Diseases; Neurons; Alzheimer Disease; Parkinson Disease
PubMed: 37259916
DOI: 10.1172/JCI168554 -
Progress in Retinal and Eye Research Nov 2022Besides cystoid macular edema due to a blood-retinal barrier breakdown, another type of macular cystoid spaces referred to as non-vasogenic cystoid maculopathies (NVCM)... (Review)
Review
Besides cystoid macular edema due to a blood-retinal barrier breakdown, another type of macular cystoid spaces referred to as non-vasogenic cystoid maculopathies (NVCM) may be detected on optical coherence tomography but not on fluorescein angiography. Various causes may disrupt retinal cell cohesion or impair retinal pigment epithelium (RPE) and Müller cell functions in the maintenance of retinal dehydration, resulting in cystoid spaces formation. Tractional causes include vitreomacular traction, epiretinal membranes and myopic foveoschisis. Surgical treatment does not always allow cystoid space resorption. In inherited retinal dystrophies, cystoid spaces may be part of the disease as in X-linked retinoschisis or enhanced S-cone syndrome, or occur occasionally as in bestrophinopathies, retinitis pigmentosa and allied diseases, congenital microphthalmia, choroideremia, gyrate atrophy and Bietti crystalline dystrophy. In macular telangiectasia type 2, cystoid spaces and cavitations do not depend on the fluid leakage from telangiectasia. Various causes affecting RPE function may result in NVCM such as chronic central serous chorioretinopathy and paraneoplastic syndromes. Non-exudative age macular degeneration may also be complicated by intraretinal cystoid spaces in the absence of fluorescein leakage. In these diseases, cystoid spaces occur in a context of retinal cell loss. Various causes of optic atrophy, including open-angle glaucoma, result in microcystoid spaces in the inner nuclear layer due to a retrograde transsynaptic degeneration. Lastly, drug toxicity may also induce cystoid maculopathy. Identifying NVCM on multimodal imaging, including fluorescein angiography if needed, allows guiding the diagnosis of the causative disease and choosing adequate treatment when available.
Topics: Humans; Glaucoma, Open-Angle; Macular Edema; Fluorescein Angiography; Macular Degeneration; Tomography, Optical Coherence; Retinal Telangiectasis
PubMed: 35927124
DOI: 10.1016/j.preteyeres.2022.101092 -
Medicina Oral, Patologia Oral Y Cirugia... 2004At present, the majority of the treatments that are performed in the clinic are due to disease entities involving the dental pulp and periapex. Dental pulp is a richly...
At present, the majority of the treatments that are performed in the clinic are due to disease entities involving the dental pulp and periapex. Dental pulp is a richly vascularized and innervated tissue, enclosed by surrounding tissues that are incapable of expanding, such as dentin. It has terminal blood flow and small-gauge circulatory access the periapex. All of these characteristics severely constrain the defensive capacity of the pulp tissue when faced with the different aggressions it may be subjected to. Pulp tissue can also be affected by a retrograde infection, arising from the secondary canaliculi, from the periodontal ligament or from the apex during the course of periodontitis. Due to the fact that periapical disease is almost inevitably preceded by pulp disease, we shall begin by describing the causes of pulp disease and will then proceed to a discussion of the causes of periapical disease. The course of illness and classification of these pathological entities will depend on the aetiology involved. We will analyse pulp necrosis and pulp degeneration that are capable of triggering reversible apical periodontitis or irreversible apical periodontitis.
Topics: Dental Pulp Necrosis; Disease Progression; Humans; Periapical Periodontitis; Pulpitis
PubMed: 15580137
DOI: No ID Found -
Autophagy Mar 2023Age-related macular degeneration (AMD), the leading cause of blindness among the elderly, is without treatment for early disease. Degenerative retinal pigment epithelial...
Age-related macular degeneration (AMD), the leading cause of blindness among the elderly, is without treatment for early disease. Degenerative retinal pigment epithelial (RPE) cell heterogeneity is a well-recognized but understudied pathogenic factor. Due to the daily phagocytosis of photoreceptor outer segments, unique photo-oxidative stress, and high metabolism for maintaining vision, the RPE has robust macroautophagy/autophagy, and mitochondrial and antioxidant networks. However, the autophagy subtype, mitophagy, in the RPE and AMD is understudied. Here, we found decreased PINK1 (PTEN induced kinase 1) in perifoveal RPE of early AMD eyes. PINK1-deficient RPE have impaired mitophagy and mitochondrial function that triggers death-resistant epithelial-mesenchymal transition (EMT). This reprogramming is mediated by novel retrograde mitochondrial-nuclear signaling (RMNS) through superoxide, NFE2L2 (NFE2 like bZIP transcription factor 2), TXNRD1 (thioredoxin reductase 1), and phosphoinositide 3-kinase (PI3K)-AKT (AKT serine/threonine kinase) that induced canonical transcription factors ZEB1 (zinc finger E-box binding homeobox 1) and SNAI1 (Snail family transcriptional repressor 1) and an EMT transcriptome. NFE2L2 deficiency disrupted RMNS that paradoxically normalized morphology but decreased function and viability. Thus, RPE heterogeneity is defined by the interaction of two cytoprotective pathways that is triggered by mitophagy function. By neutralizing the consequences of impaired mitophagy, an antioxidant dendrimer tropic for the RPE and mitochondria, EMT (a recognized AMD alteration) was abrogated to offer potential therapy for early AMD, a stage without treatment.: ACTB: actin beta; AKT: AKT serine/threonine kinase; AMD: age-related macular degeneration; CCCP: cyanide m-chlorophenyl hydrazone; CDH1: cadherin 1; DAVID: Database for Annotation, Visualization and Integrated Discovery; DHE: dihydroethidium; D-NAC: N-acetyl-l-cysteine conjugated to a poly(amido amine) dendrimer; ECAR: extracellular acidification rate; EMT: epithelial-mesenchymal transition; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSEA: Gene Set Enrichment Analysis; HSPD1: heat shock protein family D (Hsp60) member 1; IVT: intravitreal; KD: knockdown; LMNA, lamin A/C; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MMP: mitochondrial membrane potential; NAC: N-acetyl-l-cysteine; NQO1: NAD(P)H quinone dehydrogenase 1; NFE2L2: NFE2 like bZIP transcription factor 2; O: superoxide anion; OCR: oxygen consumption rate; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; RMNS: retrograde mitochondrial-nuclear signaling; ROS: reactive oxygen species; RPE: retinal pigment epithelium; SNAI1: snail family transcriptional repressor 1; TJP1: tight junction protein 1; TPP-D-NAC: triphenyl phosphinium and N-acetyl-l-cysteine conjugated to a poly(amido amine) dendrimer; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; Trig: trigonelline; TXNRD1: thioredoxin reductase 1; VIM: vimentin; WT: wild-type; ZEB1: zinc finger E-box binding homeobox 1.
Topics: Humans; Aged; Mitophagy; Autophagy; Thioredoxin Reductase 1; Antioxidants; Acetylcysteine; Dendrimers; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Retinal Pigment Epithelium; Macular Degeneration; Phosphatidylinositol 3-Kinase; Basic-Leucine Zipper Transcription Factors; Amines; Retinal Pigments; Serine
PubMed: 35921555
DOI: 10.1080/15548627.2022.2109286 -
Radiologia 2022Distal nerve degeneration refers to the process of disintegration of a neuron or neuronal circuit as a consequence of distal damage. The end result of multiple...
OBJECTIVE
Distal nerve degeneration refers to the process of disintegration of a neuron or neuronal circuit as a consequence of distal damage. The end result of multiple etiologies, this finding is becoming common due to the increasing number of imaging tests done. This paper aims to define the different types of distal nerve damage, review the anatomy and function of the most commonly affected tracts, and illustrate distal nerve damage through diagrams and representative cases from routine practice.
CONCLUSION
Knowing the distant response that can be expected according to the topography of a neuronal lesion is crucial to avoid diagnostic errors. Axonal degeneration and transsynaptic degeneration can be both antegrade and retrograde. Studies of cerebral metabolism, perfusion sequences, and diffusion sequences are showing increasingly earlier changes related to the same process; radiologists need to be aware of these changes.
Topics: Diagnostic Imaging; Humans; Nerve Degeneration; Neurons; Peripheral Nervous System Diseases
PubMed: 35504680
DOI: 10.1016/j.rxeng.2022.01.001 -
Acta Cardiologica Sinica Sep 2014Saphenous vein graft (SVG) failure secondary to degeneration can cause significant problems after coronary artery bypass surgery (CABG). Repeat revascularization by...
UNLABELLED
Saphenous vein graft (SVG) failure secondary to degeneration can cause significant problems after coronary artery bypass surgery (CABG). Repeat revascularization by percutaneous coronary intervention can be performed after SVG failure but is often associated with less favourable clinical outcome. Treatment for chronic total occlusion (CTO) of native vessels after SVG failure among patients with prior CABG is frequently performed. However, revascularization of CTO vessels in patients with prior CABG may be more complex and require more frequent use of the retrograde approach. Good septal or epicardial collateral channels are usually needed for the retrograde CTO approach. However, suitable native collateral channels may be absent and alternative retrograde routes should be considered. In this case report, we described a patient who had prior CABG and developed recurrent angina after SVG failure. His native CTO lesion was successfully revascularized by using a totally occluded vein graft as a retrograde conduit.
KEY WORDS
Chronic total occlusions; Coronary artery bypass grafts; Percutaneous coronary intervention; Saphenous vein graft.
PubMed: 27122823
DOI: No ID Found -
Frontiers in Neuroscience 2015The wobbler mouse is an animal model for human motor neuron disease, such as amyotrophic lateral sclerosis (ALS). The spontaneous, recessive wobbler mutation causes... (Review)
Review
The wobbler mouse is an animal model for human motor neuron disease, such as amyotrophic lateral sclerosis (ALS). The spontaneous, recessive wobbler mutation causes degeneration of upper and lower motor neurons leading to progressive muscle weakness with striking similarities to the ALS pathology. The wobbler mutation is a point mutation affecting Vps54, a component of the Golgi-associated retrograde protein (GARP) complex. The GARP complex is a ubiquitously expressed Golgi-localized vesicle tethering complex, tethering endosome-derived vesicles to the trans Golgi network. The wobbler point mutation leads to a destabilization of the Vps54 protein and thereby the whole GARP complex. This effectuates impairments of the retrograde vesicle transport, mis-sorting of Golgi- and endosome localized proteins and on the long run defects in Golgi morphology and function. It is currently largely unknown how the destabilization of the GARP complex interferes with the pathological hallmarks, reported for the wobbler motor neuron degeneration, like neurofilament aggregation, axonal transport defects, hyperexcitability, mitochondrial dysfunction, and how these finally lead to motor neuron death. However, the impairments of the retrograde vesicle transport and the Golgi-function appear to be critical phenomena in the molecular pathology of the wobbler motor neuron disease.
PubMed: 26539077
DOI: 10.3389/fnins.2015.00381 -
Translational Neurodegeneration Nov 2021The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%-5%...
OBJECTIVE
The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%-5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson's disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia.
METHODS
Rats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images.
RESULTS
The selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons.
CONCLUSIONS
The present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.
Topics: Animals; Astrocytes; Axons; Dopaminergic Neurons; Humans; Mice; Parkinson Disease; Rats; Rats, Sprague-Dawley; Retrograde Degeneration
PubMed: 34727977
DOI: 10.1186/s40035-021-00262-1 -
Brain Research Aug 2020Traumatic injury to the peripheral and central nervous systems very often causes axotomy, where an axon loses connections with its target resulting in loss of function.... (Review)
Review
Traumatic injury to the peripheral and central nervous systems very often causes axotomy, where an axon loses connections with its target resulting in loss of function. The axon segments distal to the injury site lose connection with the cell body and degenerate. Axotomized neurons in the periphery can spontaneously mount a regenerative response and reconnect to their denervated target tissues, though this is rarely complete in humans. In contrast, spontaneous regeneration rarely occurs after axotomy in the spinal cord and brain. Here, we concentrate on the mechanisms underlying this spontaneous regeneration in the peripheral nervous system, focusing on events initiated from the axon that support regenerative growth. We contrast this with what is known for axonal injury responses in the central nervous system. Considering the neuropathy focus of this special issue, we further draw parallels and distinctions between the injury-response mechanisms that initiate regenerative gene expression programs and those that are known to trigger axon degeneration.
Topics: Animals; Axons; Axotomy; Humans; Nerve Regeneration; Peripheral Nervous System Diseases; RNA; Spinal Cord Injuries
PubMed: 32360100
DOI: 10.1016/j.brainres.2020.146864