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Motor Neuron Death (motor + neuron_death)
Selected AbstractsRecombinant human erythropoietin suppresses symptom onset and progression of G93A-SOD1 mouse model of ALS by preventing motor neuron death and inflammationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2007Seong-Ho Koh Abstract Multifactorial pathogenic mechanisms, including inflammation, attenuated survival signals and enhanced death signals, are involved in amyotrophic lateral sclerosis (ALS). Erythropoietin (EPO) has recently been highlighted as a cytokine with various potent neuroprotective effects, including reduction of inflammation, enhancement of survival signals and prevention of neuronal cell death. This study was undertaken to evaluate the effect of recombinant human EPO (rhEPO) on ALS model mice. We treated 96 ALS model mice with vehicle only, or 1, 2.5 or 5 iµ of rhEPO/g of mouse once every other week after they were 60 days old. The treatment significantly prolonged symptom onset and life span, preserved more motor neurons, enhanced survival signals, and attenuated inflammatory signals in a dose-dependent manner. These data suggest that treatment with rhEPO represents a potential therapeutic strategy for ALS. [source] Amyotrophic lateral sclerosis: all roads lead to RomeJOURNAL OF NEUROCHEMISTRY, Issue 5 2007Jose-Luis Gonzalez de Aguilar Abstract Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease characterized by degeneration of upper and lower motor neurons, generalized weakness and muscle atrophy. Most cases of ALS appear sporadically but some forms of the disease result from mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1). Several other mutated genes have also been found to predispose to ALS including, among others, one that encodes the regulator of axonal retrograde transport dynactin. As all roads lead to the proverbial Rome, we discuss here how distinct molecular pathways may converge to the same final result that is motor neuron death. We critically review the basic research on SOD1-linked ALS to propose a pioneering model of a ,systemic' form of the disease, causally involving multiple cell types, either neuronal or non-neuronal. Contrasting this, we also postulate that other neuron-specific defects, as those triggered by dynactin dysfunction, may account for a primary motor neuron disease that would represent ,pure' neuronal forms of ALS. Identifying different disease subtypes is an unavoidable step toward the understanding of the physiopathology of ALS and will hopefully help to design specific treatments for each subset of patients. [source] Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosisJOURNAL OF NEUROCHEMISTRY, Issue 5 2002Makoto Urushitani Abstract Accumulating evidence indicates that abnormal conformation of mutant superoxide dismutase 1 (SOD1) is an essential feature underlying the pathogenesis of mutant SOD1-linked familial amyotrophic lateral sclerosis (ALS). Here we investigated the role of ubiquitin-proteasome pathway in the mutant SOD1-related cell death and the effect of oxidative stress on the misfolding of mutant SOD1. Transient overexpression of ubiquitin with human SOD1 (wild-type, ala4val, gly85arg, gly93ala) in Neuro2A cells decreased the amount of mutant SOD1, but not of wild-type, while only mutants were co-immunoprecipitated with poly-ubiquitin. Proteasome inhibition by lactacystin augmented accumulation of mutant SOD1 in the non-ionic detergent-insoluble fraction. The spinal cord lysates from mutant SOD1 transgenic mice showed multiple carbonylated proteins, including mutant SOD1 with SDS-resistant dimer formation. Furthermore, the treatment of hSOD1-expressing cells with hydrogen peroxide promoted the oligomerization, and detergent-insolubility of mutant SOD1 alone, and the oxidized mutant SOD1 proteins were more heavily poly-ubiquitinated. In Neuro2A cells stably expressing human SOD1 protein, the proteasome function measured by chymotrypsin-like activity, was decreased over time without a quantitative alteration of the 20S proteasomal component. Finally, primary motor neurons from the mouse embryonic spinal cord were more vulnerable to lactacystin than non-motor neurons. These results indicate that the sustained expression of mutant SOD1 leads to proteasomal inhibition and motor neuronal death, which in part explains the pathogenesis of mutant SOD1-linked ALS. [source] Prevention of spinal motor neuron death by insulin-like growth factor-1 associating with the signal transduction systems in SODG93A transgenic miceJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2005Hisashi Narai Abstract The role of insulin-like growth factor-1 (IGF-1) in amyotrophic lateral sclerosis (ALS) and its mechanism of action are important from both pathogenic and therapeutic points of view. The present study investigated the changes of IGF-1R, and the key intracellular downstream protein insulin receptor substrate-1 (IRS-1) by using SOD1G93A transgenic mice with continuous intrathecal IGF-1 treatment. The number of lumbar spinal motor neurons was preserved with IGF-1 treatment in a dose-dependent manner. The numbers of immunopositive motor neurons for IGF-1R, and IRS-1 were not significantly different between wild-type and Tg mice with vehicle treatment, whereas treatment of Tg mice with IGF-1 decreased the numbers of immunopositive motor neurons in a dose-dependent manner. On the other hand, the ratio of immunopositive motor neurons per total living motor neurons in vehicle-treated mice was greatly increased in Tg mice with vehicle treatment compared with wild-type mice. With IGF-1 treatment, the ratio was dramatically decreased in a dose-dependent manner. These results suggest that IGF-1 treatment prevents motor neuron loss by affecting the signal transduction system through IGF-1R and the main downstream signal, IRS-1. © 2005 Wiley-Liss, Inc. [source] Glia cells in amyotrophic lateral sclerosis: New clues to understanding an old disease?MUSCLE AND NERVE, Issue 6 2007Clemens Neusch MD Abstract In classic neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), the pathogenic concept of a cell-autonomous disease of motor neurons has been challenged increasingly in recent years. Macro- and microglial cells have come to the forefront for their role in multistep degenerative processes in ALS and respective disease models. The activation of astroglial and microglial cells occurs early in the pathogenesis of the disease and seems to greatly influence disease onset and promotion. The role of oligodendrocytes and Schwann cells remains elusive. In this review we highlight the impact of nonneuronal cells in ALS pathology. We discuss diverse glial membrane proteins that are necessary to control neuronal activity and neuronal cell survival, and summarize the contribution of these proteins to motor neuron death in ALS. We also describe recently discovered glial mechanisms that promote motor neuron degeneration using state-of-the-art genetic mouse technology. Finally, we provide an outlook on the extent to which these new pathomechanistic insights may offer novel therapeutic approaches. Muscle Nerve, 2007 [source] Hind-limb paraparesis in a rat model for neurolathyrism associated with apoptosis and an impaired vascular endothelial growth factor system in the spinal cordTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 6 2010Kuniko Kusama-Eguchi Abstract Neurolathyrism is a motor neuron disease characterized by lower limb paraparesis. It is associated with ingestion of a plant excitotoxin, ,-N-oxalyl-L-,,-diaminopropionic acid (L -,-ODAP), an agonist of ,-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-type glutamatergic receptors. Previously, a limited model of neurolathyrism was reported for the rat. To improve upon the model, we stressed rat pups by separation from their mothers, followed by the subcutaneous L -,-ODAP treatment, resulting in a 4.6-fold higher incidence (14.0,15.6%) of the paraparesis compared with the prior study. The number and size of motor neurons in these rats were decreased only in the lumbar and sacral cord segments, at approximately 13,36 weeks after treatment. Only lumbar and sacral spinal cord tissue revealed pathological insults typical of physical and ischemic spinal cord injury in the surviving motor neurons. In addition, extensive but transient hemorrhage occurred in the ventral spinal cord parenchyma of the rat, and numerous TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive cells were also observed. In parallel, vascular endothelial growth factor receptor (VEGFR)-2 (Flk-1) levels were significantly lowered in the lumbosacral spinal cord of the paraparetic rats compared with their controls, suggesting a failure of the VEGF system to protect neurons against L -,-ODAP toxicity. We propose, based on these data, a novel pathological process of motor neuron death induced by peripheral L -,-ODAP. For the first time, we present a model of the early molecular events that occur during chemically induced spinal cord injury, which can potentially be applied to other neurodegenerative disorders. J. Comp. Neurol. 518:928,942, 2010. © 2009 Wiley-Liss, Inc. [source] | ||||||||||