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axon degeneration

Shandiz Tehrani, R Katherine Delf, William O Cepurna, Lauren Davis, Elaine C Johnson, John C Morrison
Small molecule delivery to the optic nerve would allow for exploration of molecular and cellular pathways involved in normal physiology and optic neuropathies such as glaucoma, and provide a tool for screening therapeutics in animal models. We report a novel surgical method for small molecule drug delivery to the optic nerve head (ONH) in a rodent model. In proof-of-principle experiments, we delivered cytochalasin D (Cyt D; a filamentous actin inhibitor) to the junction of the superior optic nerve and globe in rats to target the actin-rich astrocytic cytoskeleton of the ONH...
March 13, 2018: Scientific Reports
Nirupa D Jayaraj, Bula J Bhattacharyya, Abdelhak A Belmadani, Dongjun Ren, Craig A Rathwell, Sandra Hackelberg, Brittany E Hopkins, Herschel R Gupta, Richard J Miller, Daniela M Menichella
Painful diabetic neuropathy (PDN) is an intractable complication of diabetes that affects 25% of patients. PDN is characterized by neuropathic pain and small-fiber degeneration, accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability and loss of their axons within the skin. The molecular mechanisms underlying DRG nociceptor hyperexcitability and small-fiber degeneration in PDN are unknown. We hypothesize that chemokine CXCL12/CXCR4 signaling is central to this mechanism, as we have shown that CXCL12/CXCR4 signaling is necessary for the development of mechanical allodynia, a pain hypersensitivity behavior common in PDN...
March 13, 2018: Journal of Clinical Investigation
Priscila A C Valadão, Matheus P S M Gomes, Bárbara C Aragão, Hermann A Rodrigues, Jéssica N Andrade, Rubens Garcias, Julliane V Joviano-Santos, Murilo A Luiz, Wallace L Camargo, Lígia A Naves, Christopher Kushmerick, Walter L G Cavalcante, Márcia Gallacci, Itamar C G de Jesus, Silvia Guatimosim, Cristina Guatimosim
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by chorea, incoordination, and psychiatric and behavioral symptoms. The leading cause of death in HD patients is aspiration pneumonia, associated with respiratory dysfunction, decreased respiratory muscle strength and dysphagia. Although most of the motor symptoms are derived from alterations in the central nervous system, some might be associated with changes in the components of motor units (MU). To explore this hypothesis, we evaluated morphofunctional aspects of the diaphragm muscle in a mouse model of HD (BACHD)...
March 9, 2018: Neurochemistry International
Menuka Pallebage-Gamarallage, Sean Foxley, Ricarda A L Menke, Istvan N Huszar, Mark Jenkinson, Benjamin C Tendler, Chaoyue Wang, Saad Jbabdi, Martin R Turner, Karla L Miller, Olaf Ansorge
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a clinically and histopathologically heterogeneous neurodegenerative disorder, in which therapy is hindered by the rapid progression of disease and lack of biomarkers. Magnetic resonance imaging (MRI) has demonstrated its potential for detecting the pathological signature and tracking disease progression in ALS. However, the microstructural and molecular pathological substrate is poorly understood and generally defined histologically...
March 13, 2018: BMC Neuroscience
Giuseppe Battaglia, Valeria Bruno
Amyotrophic lateral sclerosis (ALS) is a complex genetic, late age-onset, progressive neurodegenerative disorder leading to the death of upper and lower motor neurons. Life expectancy after diagnosis is short due to the ongoing degeneration and to the lack of effective treatments. Axonal alterations, mitochondrial deficits, RNA changes, protein misfolding and turnover, glial dysfunction and hyperexcitability are key players in molecular mechanisms involved in the degeneration of motor neurons. In the context of hyperexcitability, metabotropic glutamate (mGlu) receptors, which are widely distributed throughout the central nervous system and act through many intracellular signaling pathways, are emerging as novel potential drug targets for the therapeutic treatment of ALS, as they are able to counteract excitotoxicity by reducing glutamate release and inducing the production of neurotrophic factors...
March 9, 2018: Current Opinion in Pharmacology
Wen Yin, Xing Li, Yannan Zhao, Jun Tan, Shuyu Wu, Yudong Cao, Juan Li, Hecheng Zhu, Weidong Liu, Guihua Tang, Li Meng, Lei Wang, Bin Zhu, Gousiyi Wang, Meizuo Zhong, Xingdong Liu, Dan Xie, Bing Chen, Caiping Ren, Zhifeng Xiao, Xingjun Jiang, Jianwu Dai
Treatment of spinal cord injury (SCI) remains a clinical challenge worldwide because of the complicated inhibitory microenvironment formed post-injury, reduced axonal regenerative ability of spinal cord neurons, and scarcity of endogenous neurogenesis within the lesion center. Taxol, in addition to stabilizing microtubules, has shown potential for decreasing axonal degeneration and reducing scar formation after SCI in rodents. In this study, we further verified the therapeutic effects and clinical potential of Taxol on restriction of scar formation and promotion of neuronal regeneration and functional recovery after severe spinal cord transection in a large animal (canine) model...
March 12, 2018: Biomaterials Science
Sanuji Gajamange, David Raffelt, Thijs Dhollander, Elaine Lui, Anneke van der Walt, Trevor Kilpatrick, Joanne Fielding, Alan Connelly, Scott Kolbe
Long term irreversible disability in multiple sclerosis (MS) is thought to be primarily driven by axonal degeneration. Axonal degeneration leads to degenerative atrophy, therefore early markers of axonal degeneration are required to predict clinical disability and treatment efficacy. Given that additional pathologies such as inflammation, demyelination and oedema are also present in MS, it is essential to develop axonal markers that are not confounded by these processes. The present study investigated a novel method for measuring axonal degeneration in MS based on high angular resolution diffusion magnetic resonance imaging...
2018: NeuroImage: Clinical
Carrie J Finno, Matthew H Bordbari, Giuliana Gianino, Brittni Ming-Whitfield, Erin Burns, Janel Merkel, Monica Britton, Blythe Durbin-Johnson, Erica A Sloma, Marissa McMackin, Gino Cortopassi, Victor Rivas, Marietta Barro, Cecilia K Tran, Ingrid Gennity, Hadi Habib, Libin Xu, Birgit Puschner, Andrew D Miller
Mice with deficiency in tocopherol (alpha) transfer protein gene develop peripheral tocopherol deficiency and sensory neurodegeneration. Ttpa-/- mice maintained on diets with deficient α-tocopherol (α-TOH) had proprioceptive deficits by six months of age, axonal degeneration and neuronal chromatolysis within the dorsal column of the spinal cord and its projections into the medulla. Transmission electron microscopy revealed degeneration of dorsal column axons. We addressed the potential pathomechanism of α-TOH deficient neurodegeneration by global transcriptome sequencing within the spinal cord and cerebellum...
March 8, 2018: Free Radical Biology & Medicine
Kimberly A Fernandes, Katherine L Mitchell, Amit Patel, Olivia J Marola, Peter Shrager, Donald J Zack, Richard T Libby, Derek S Welsbie
Optic neuropathies such as glaucoma are characterized by the degeneration of retinal ganglion cells (RGCs) and the irreversible loss of vision. In these diseases, focal axon injury triggers a propagating axon degeneration and, eventually, cell death. Previous work by us and others identified dual leucine zipper kinase (DLK) and JUN N-terminal kinase (JNK) as key mediators of somal cell death signaling in RGCs following axonal injury. Moreover, others have shown that activation of the DLK/JNK pathway contributes to distal axonal degeneration in some neuronal subtypes and that this activation is dependent on the adaptor protein, sterile alpha and TIR motif containing 1 (SARM1)...
March 8, 2018: Experimental Eye Research
T Gabriel Enge, Heath Ecroyd, Dianne F Jolley, Justin J Yerbury, Bernadett Kalmar, Anthony Dosseto
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is among the most common of the motor neuron diseases, and arguably the most devastating. During the course of this fatal neurodegenerative disorder, motor neurons undergo progressive degeneration. The currently best-understood animal models of ALS are based on the over-expression of mutant isoforms of Cu/Zn superoxide dismutase 1 (SOD1); these indicate that there is a perturbation in metal homeostasis with disease progression. Copper metabolism in particular is affected in the central nervous system (CNS) and muscle tissue...
March 7, 2018: Molecular and Cellular Neurosciences
Stuart J Grice, James N Sleigh, M Zameel Cader
Dominant mutations in GARS , encoding the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and Charcot-Marie-Tooth disease type 2D (CMT2D). This genetic disorder exemplifies a recurring paradigm in neurodegeneration, in which mutations in essential genes cause selective degeneration of the nervous system. Recent evidence suggests that the mechanism underlying CMT2D involves extracellular neomorphic binding of mutant GlyRS to neuronally-expressed proteins. Consistent with this, our previous studies indicate a non-cell autonomous mechanism, whereby mutant GlyRS is secreted and interacts with the neuromuscular junction (NMJ)...
2018: Frontiers in Molecular Neuroscience
Zhongying Mo, Xiaobei Zhao, Huaqing Liu, Qinghua Hu, Xu-Qiao Chen, Jessica Pham, Na Wei, Ze Liu, Jiadong Zhou, Robert W Burgess, Samuel L Pfaff, C Thomas Caskey, Chengbiao Wu, Ge Bai, Xiang-Lei Yang
Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease's specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset...
March 8, 2018: Nature Communications
Massimo Dal Monte, Maurizio Cammalleri, Filippo Locri, Rosario Amato, Stefania Marsili, Dario Rusciano, Paola Bagnoli
Optic neuritis is an acute inflammatory demyelinating disorder of the optic nerve (ON) and is an initial symptom of multiple sclerosis (MS). Optic neuritis is characterized by ON degeneration and retinal ganglion cell (RGC) loss that contributes to permanent visual disability and lacks a reliable treatment. Here, we used the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, a well-established model also for optic neuritis. In this model, C57BL6 mice, intraperitoneally injected with a fragment of the myelin oligodendrocyte glycoprotein (MOG), were found to develop inflammation, Müller cell gliosis, and infiltration of macrophages with increased production of oncomodulin (OCM), a calcium binding protein that acts as an atypical trophic factor for neurons enabling RGC axon regeneration...
March 8, 2018: Nutrients
Liancai Mu, Jingming Chen, Jing Li, Themba Nyirenda, Mary Fowkes, Stanislaw Sobotka
BACKGROUND:  We have demonstrated that the native motor zone (NMZ) within a muscle is an ideal target for performing nerve-muscle-endplate band grafting (NMEG) to restore motor function of a denervated muscle. This study was designed to determine spatiotemporal alterations of the myofibers, motor endplates (MEPs), and axons in the NMZ of long-term denervated muscles for exploring if NMEG-NMZ technique would have the potential for delayed reinnervation. METHODS:  Sternomastoid (SM) muscles of adult female Sprague-Dawley rats ( n  = 21) were experimentally denervated and denervation-induced changes in muscle weight, myofiber size, MEPs, and intramuscular nerve axons were evaluated histomorphometrically and immunohistochemically at the end of 3, 6, and 9 months after denervation...
March 6, 2018: Journal of Reconstructive Microsurgery
Bum-Soo Kim, Joon-Hyuk Choi, Suk-Hwan Baek, Deok-Hee Lee
BACKGROUND AND OBJECTIVES: Dexmedetomidine is known to have neural protection effect via attenuation of inflammatory responses induced by local anesthetics. We investigated whether intraneural dexmedetomidine is effective for attenuating or preventing neural injury resulting from inadvertent intraneural injection of local anesthetic. METHODS: Rats were randomly divided, and left sciatic nerve was surgically exposed. The rats received no injection (control group) or intraneural injections of 0...
March 3, 2018: Regional Anesthesia and Pain Medicine
Anu Paul, Manuel Comabella, Roopali Gandhi
Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease with a complex clinical course characterized by inflammation, demyelination, and axonal degeneration. Diagnosis of MS most commonly includes finding lesions in at least two separate areas of the central nervous system (CNS), including the brain, spinal cord, and optic nerves. In recent years, there has been a remarkable increase in the number of available treatments for MS. An optimal treatment is usually based on a personalized approach determined by an individual patient's prognosis and treatment risks...
March 2, 2018: Cold Spring Harbor Perspectives in Medicine
Tae Chung, Yanli Tian, Jeremy Walston, Ahmet Hoke
OBJECTIVE: Age-associated skeletal muscle weakness is a major contributing factor to an increased late life mortality and morbidity, but its neurobiology is poorly understood. Previously, we provided histological evidence of dying-back axonal degeneration of motor neurons and denervation of neuromuscular junctions (NMJ) in age-associated muscle weakness. Given this, we aim to evaluate the relation between impaired neuromuscular transmission and various aspects of age-associated muscle weakness...
March 1, 2018: American Journal of Physical Medicine & Rehabilitation
Victor S C Wong, Cristina Picci, Michelle Swift, Max Levinson, Dianna Willis, Brett Langley
Damage to the CNS results in neuronal and axonal degeneration, and subsequent neurological dysfunction. Endogenous repair in the CNS is impeded by inhibitory chemical and physical barriers, such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated glycoprotein (MAG), which prevent axon regeneration. Previously, it has been demonstrated that the inhibition of axonal histone deacetylase-6 (HDAC6) can promote microtubule α-tubulin acetylation and restore the growth of CSPGs- and MAG-inhibited axons...
January 2018: ENeuro
Nathalie Bernard-Marissal, Roman Chrast, Bernard L Schneider
Recent progress in the understanding of neurodegenerative diseases revealed that multiple molecular mechanisms contribute to pathological changes in neurons. A large fraction of these alterations can be linked to dysfunction in the endoplasmic reticulum (ER) and mitochondria, affecting metabolism and secretion of lipids and proteins, calcium homeostasis, and energy production. Remarkably, these organelles are interacting with each other at specialized domains on the ER called mitochondria-associated membranes (MAMs)...
February 28, 2018: Cell Death & Disease
Christina F Vogelaar, Shibajee Mandal, Steffen Lerch, Katharina Birkner, Jerome Birkenstock, Ulrike Bühler, Andrea Schnatz, Cedric S Raine, Stefan Bittner, Johannes Vogt, Jonathan Kipnis, Robert Nitsch, Frauke Zipp
Ongoing axonal degeneration is thought to underlie disability in chronic neuroinflammation, such as multiple sclerosis (MS), especially during its progressive phase. Upon inflammatory attack, axons undergo pathological swelling, which can be reversible. Because we had evidence for beneficial effects of T helper 2 lymphocytes in experimental neurotrauma and discovered interleukin-4 receptor (IL-4R) expressed on axons in MS lesions, we aimed at unraveling the effects of IL-4 on neuroinflammatory axon injury. We demonstrate that intrathecal IL-4 treatment during the chronic phase of several experimental autoimmune encephalomyelitis models reversed disease progression without affecting inflammation...
February 28, 2018: Science Translational Medicine
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