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1.
Ornella Spadoni Alessio Crestini Paola Piscopo Lorenzo Malvezzi-Campeggi Irene Carunchio Massimo Pieri Cristina Zona Annamaria Confaloni 《Cellular and molecular neurobiology》2009,29(5):635-641
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease defined by motor neuron loss. Transgenic mouse
model (Tg SOD1G93A) shows pathological features that closely mimic those seen in ALS patients. An hypothetic link between
AD and ALS was suggested by finding an higher amount of amyloid precursor protein (APP) in the spinal cord anterior horn neurons,
and of Aβ peptides in ALS patients skin. In this work, we have investigated the expression of some genes involved in Alzheimer’s
disease, as APP, β- and γ-secretase, in an animal model of ALS, to understand some possible common molecular mechanisms between
these two pathologies. For gene expression analysis, we carried out a quantitative RT-PCR in ALS mice and in transgenic mice
over-expressing human wild-type SOD1 (Tg hSOD1). We found that APP and BACE1 mRNA levels were increased 1.5-fold in cortical
cells of Tg SOD1G93A mice respect to Tg hSOD1, whereas the expression of γ-secretase genes, as PSEN1, PSEN2, Nicastrin, and
APH1a, showed no statistical differences between wild-type and ALS mice. Biochemical analysis carried out by immunostaining
and western blotting, did not show any significant modulation of the protein expression compared to the genes, suggesting
the existence of post-translational mechanisms that modify protein levels. 相似文献
2.
Ekaterini Kefalakes Sebastian Böselt Anastasia Sarikidi Miren Ettcheto Franziska Bursch Maximilian Naujock Nancy Stanslowsky Martin Schmuck Marta Barenys Florian Wegner Claudia Grothe Susanne Petri 《Journal of cellular physiology》2019,234(5):7395-7410
We have previously shown that knockout of fibroblast growth factor-2 (FGF-2) and potential compensatory effects of other growth factors result in amelioration of disease symptoms in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive neurological disorder leading to degeneration of cortical, brain stem, and spinal motor neurons followed by subsequent denervation and muscle wasting. Mutations in the superoxide dismutase 1 (SOD1) gene are responsible for approximately 20% of familial ALS cases and SOD1 mutant mice still are among the models best mimicking clinical and neuropathological characteristics of ALS. The aim of the present study was a thorough characterization of FGF-2 and other growth factors and signaling effectors in vivo in the SOD1G93A mouse model. We observed tissue-specific opposing gene regulation of FGF-2 and overall dysregulation of other growth factors, which in the gastrocnemius muscle was associated with reduced downstream extracellular-signal-regulated kinases (ERK) and protein kinase B (AKT) activation. To further investigate whether the effects of FGF-2 on motor neuron death are mediated by glial cells, astrocytes lacking FGF-2 were cocultured together with mutant SOD1 G93A motor neurons. FGF-2 had an impact on motor neuron maturation indicating that astrocytic FGF-2 affects motor neurons at a developmental stage. Moreover, neuronal gene expression patterns showed FGF-2- and SOD1 G93A-dependent changes in ciliary neurotrophic factor, glial-cell-line-derived neurotrophic factor, and ERK2, implying a potential involvement in ALS pathogenesis before the onset of clinical symptoms. 相似文献
3.
Sara OLIVáN Ana Cristina CALVO Amaya RANDO María Jesús MU?OZ Pilar ZARAGOZA Rosario OSTA 《Experimental Animals》2015,64(2):147-153
In preclinical trials, a sensitive functional test is required to detect changes in the
motor behaviour of the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS). We
evaluated changes in body weight and motor impairment in behavioural tests, such as the
rotarod, the hanging-wire test and the treadmill, of transgenic and wild type mice. We
found differences in detection of the onset of symptoms and progression of the disease
between the different tests assessed. Moreover, the data showed significant gender
differences in the motor behaviour of this mouse model. The rotarod and the hanging-wire
test were more sensitive to detect early motor impairment. Moreover, the results suggested
that the rotarod and hanging-wire became the most accurate tests rather than treadmill to
characterise the ALS disease phenotype. 相似文献
4.
Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are caused by mutations in the super oxide dismutase 1 (SOD1) gene and transgenic mice for these mutations recapitulate many features of this devastating neurodegenerative disease. Here we show that the amount of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), two endocannabinoids that have neuroprotective properties, increase in spinal cord of SOD1(G93A) transgenic mice. This increase occurs in the lumbar section of spinal cords, the first section to undergo neurodegeneration, and is significant before overt motor impairment. Our results show that chronic neurodegeneration induced by a genetic mutation increases endocannabinoid production possibly as part of an endogenous defense mechanism. 相似文献
5.
Yansu Guo Weisong Duan Zhongyao Li Jing Huang Yunxia Yin Qian Wang Chunyan Li 《FEBS letters》2010,584(8):1615-1622
The SOD1-G93A transgenic mouse is a widely used ALS model, but the death of lower motor neurons is the hallmark. Here, we show that the SOD1-G93A transgene and HO-1 are preferentially over-expressed in the lumbar spinal cord, particularly in the activated astrocytes of the transgenic mice. We also show down-regulation of GLT-1 in spite of the proliferating astrocytes. However, GLT-1, SOD1-G93A transgene and HO-1 expression were not obviously changed in the motor cortex. Our data link spinal cord vulnerability to relatively decreased expression of GLT-1, and high expression of the transgene and HO-1 in astrocytes in SOD1-G93A transgenic mice. 相似文献
6.
Junghee Lee Hoon Ryu Neil W. Kowall 《Biochemical and biophysical research communications》2009,384(4):524-529
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to motor neuron degeneration. Despite the fact that many different therapeutic strategies have been applied to prevent disease progression, no cure or effective therapy is currently available for ALS. We found that l-arginine protects cultured motor neurons from excitotoxic injury. We also found that l-arginine supplementation both prior to and after the onset of motor neuron degeneration in mtSOD1 (G93A) transgenic ALS mice significantly slowed the progression of neuropathology in lumbar spinal cord, delayed onset of motor dysfunction, and prolonged life span. Moreover, l-arginine treatment was associated with preservation of arginase I activity and neuroprotective polyamines in spinal cord motor neurons. Our findings show that l-arginine has potent in vitro and in vivo neuroprotective properties and may be a candidate for therapeutic trials in ALS. 相似文献
7.
Rana Lee Jane Melissa Lim Kyung-Hye Roh Ji Hyun Kim Seongman Kang 《Animal cells and systems.》2016,20(6):310-316
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with the selective loss of motor neurons in the brain, brain stem, and spinal cord. A number of the mutants of the human gene for superoxide dismutase 1 (SOD1) have been shown to cause familial ALS as a result of gain-of-function toxicity by an unknown mechanism. In this study, we show that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) functions as a critical mediator of the apoptotic cell death signaling cascade induced by the ALS-associated G93A mutant of human SOD1 [SOD1(G93A)]. We observed that SOD1(G93A) induces S-nitrosylation of GAPDH and the subsequent binding of GAPDH and Siah1 in NSC34 motor neuron-like cells. Furthermore, SOD1(G93A) promoted nuclear translocation of S-nitrosylated GAPDH in the cells. In addition, SOD1(G93A)-induced apoptotic cell death was inhibited by deprenyl, a chemical inhibitor of GAPDH S-nitrosylation, in NSC34 cells. Taken together, our findings suggest that S-nitrosylation of GAPDH plays a critical role in SOD1(G93A)-induced neuronal apoptosis. 相似文献
8.
Sung Eun Sim Yoon Hee Chung Ji Hoon Jeong Sin Weon Yun Hyoun-Sub Lim Daejin Kim Sung Su Kim Won Bok Lee Choong Ik Cha 《Journal of molecular histology》2009,40(2):157-163
In the present study, we performed immunohistochemical studies to investigate the changes of insulin-like growth factor binding
protein 2 (IGFBP2) in the central nervous system of SOD1G93A mutant transgenic mice as an in vivo model of amyotrophic lateral sclerosis (ALS). Decreased immunoreactivity for IGFBP2
was observed in the cerebral cortex, hippocampus and brainstem of SOD1G93A transgenic mice. In the cerebral cortex, the number of IGFBP2-positive cells was decreased in the somatomotor area, somatosensory
area, auditory area, visual area, entorhinal area, piriform area and prefrontal area. In the hippocampal formation, IGFBP2
immunoreactivity was significantly decreased in the CA1-3 areas and the dentate gyrus. In the brainstem, few IGFBP2-immunoreactive
cells were observed in the medullary and pontine reticular formation, vestibular nucleus, trigeminal motor nucleus, facial
nucleus, hypoglossal nucleus and raphe nucleus. In the spinal cord, IGFBP2 immunoreactivity was not significantly decreased
in SOD1G93A transgenic mice. This study showing decreased IGFBP2 in different brain regions of SOD1G93A transgenic mice may provide clues for understanding differential susceptibility of neural structures in ALS.
S. E. Sim and Y. H. Chung have contributed equally to this work. 相似文献
9.
10.
Chen T Benmohamed R Arvanites AC Ralay Ranaivo H Morimoto RI Ferrante RJ Watterson DM Kirsch DR Silverman RB 《Bioorganic & medicinal chemistry》2011,19(1):613-622
Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. Mutations in copper/zinc superoxide dismutase 1 (SOD1) have been implicated in the pathophysiology of this disease. Using a high-throughput screening assay expressing mutant G93A SOD1, two bioactive chemical hit compounds (1 and 2), identified as arylsulfanyl pyrazolones, were identified. The structural optimization of this scaffold led to the generation of a more potent analogue (19) with an EC50 of 170 nM. To determine the suitability of this class of compounds for further optimization, 1 was subjected to a battery of pharmacokinetic assays; most of the properties of 1 were good for a screening hit, except it had a relatively rapid clearance and short microsomal half-life stability. Compound 2 was found to be blood-brain barrier penetrating with a brain/plasma ratio = 0.19. The optimization of this class of compounds could produce novel therapeutic candidates for ALS patients. 相似文献
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12.
Shin JH Lee YA Lee JK Lee YB Cho W Im DS Lee JH Yun BS Springer JE Gwag BJ 《Journal of neurochemistry》2012,122(5):952-961
J. Neurochem. (2012) 122, 952-961. ABSTRACT: While free radicals and inflammation constitute major routes of neuronal injury occurring in amyotrophic lateral sclerosis (ALS), neither antioxidants nor non-steroidal anti-inflammatory drugs have shown significant efficacy in human clinical trials. We examined the possibility that concurrent blockade of free radicals and prostaglandin E(2) (PGE(2) )-mediated inflammation might constitute a safe and effective therapeutic approach to ALS. We have developed 2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] (AAD-2004) as a derivative of aspirin. AAD-2004 completely removed free radicals at 50?nM as a potent spin-trapping molecule and inhibited microsomal PGE(2) synthase-1 (mPGES-1) activity in response to both lipopolysaccharide-treated BV2 cell with IC(50) of 230?nM and recombinant human mPGES-1 protein with IC(50) of 249?nM in vitro. In superoxide dismutase 1(G93A) transgenic mouse model of ALS, AAD-2004 blocked free radical production, PGE(2) formation, and microglial activation in the spinal cords. As a consequence, AAD-2004 reduced autophagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span. In these assays, AAD-2004 was superior to riluzole or ibuprofen. Gastric bleeding was not induced by AAD-2004 even at a dose 400-fold higher than that required to obtain maximal therapeutic efficacy in superoxide dismutase 1(G93A) . Targeting both mPGES-1-mediated PGE(2) and free radicals may be a promising approach to reduce neurodegeneration in ALS and possibly other neurodegenerative diseases. 相似文献
13.
Ali Morsi El-Kadi Virginie Bros-Facer Wenhan Deng Amelia Philpott Eleanor Stoddart Gareth Banks Graham S. Jackson Elizabeth M. C. Fisher Michael R. Duchen Linda Greensmith Anthony L. Moore Majid Hafezparast 《The Journal of biological chemistry》2010,285(24):18627-18639
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute ∼10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15–20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord. We have previously shown that the autosomal dominant Legs at odd angles (Loa) mutation in cytoplasmic dynein heavy chain (Dync1h1) delays disease onset and extends the life span of transgenic mice harboring human mutant SOD1G93A. In this study we provide evidence that despite the lack of direct interactions between mutant SOD1 and either mutant or wild-type cytoplasmic dynein, the Loa mutation confers significant reductions in the amount of mutant SOD1 protein in the mitochondrial matrix. Moreover, we show that the Loa mutation ameliorates defects in mitochondrial respiration and membrane potential observed in SOD1G93A motor neuron mitochondria. These data suggest that the Loa mutation reduces the vulnerability of mitochondria to the toxic effects of mutant SOD1, leading to improved mitochondrial function in SOD1G93A motor neurons. 相似文献
14.
The influence of stimulus pulse duration on calcium mobilization triggering facilitation of evoked [(3)H]acetylcholine ([(3)H]ACh) release by the A(2A) adenosine receptor agonist CGS 21680C was studied in the rat phrenic nerve-hemidiaphragm. The P-type calcium channel blocker omega-agatoxin IVA (100 nM) decreased [(3)H]ACh release evoked with pulses of 0.04-ms duration, whereas nifedipine (1 microM) inhibited transmitter release with pulses of 1-ms duration. Depletion of intracellular calcium stores by thapsigargin (2 microM) decreased [(3)H]ACh release evoked by pulses of 1 ms, an effect observed even in the absence of extracellular calcium. With short (0.04-ms) stimulation pulses, when P-type calcium influx triggered transmitter release, facilitation of [(3)H]ACh release by CGS 21680C (3 nM) was attenuated by both thapsigargin (2 microM) and nifedipine (1 microM). With longer stimuli (1 ms), a situation in which both thapsigargin-sensitive internal stores and L-type channels are involved in ACh release, pretreatment with either omega-agatoxin IVA (100 nM) or nifedipine (1 microM) reduced the facilitatory effect of CGS 21680C (3 nM). The results suggest that A(2A) receptor activation facilitates ACh release from motor nerve endings through alternatively mobilizing the available calcium pools (thapsigargin-sensitive internal stores and/or P- or L-type channels) that are not committed to the release process in each stimulation condition. 相似文献
15.
Ruiz MA Escriche M Lluis C Franco R Martín M Andrés A Ros M 《Journal of neurochemistry》2000,75(2):656-664
Adenosine A(1) receptors (A(1)Rs) have been characterized in primary cultures of neurons from cerebral cortex. The specific adenosine A(1) antagonist 8-cyclopentyl-1,3-[(3)H]dipropylxanthine bound to both membranes and intact cells. When saturation experiments were performed in membranes, a K(D) value of 0.76 nM and a B(max) of 57 fmol/mg of protein were obtained. Competition assays revealed a pharmacological profile characteristic of A(1)Rs. The presence of this receptor was further confirmed by RT-PCR analysis. The expression of the receptor showed no significant changes during the period of culture studied, up to 12 days in vitro. A(1)R agonist inhibited forskolin-stimulated adenylyl cyclase, showing the functional coupling of these receptors with the effector. alphaG(i1, 2) protein level, detected by immunoblot, presented an increase during the period of culture. This increase correlated with an increase in the mRNA level of alphaG(i1) but not alphaG(i2). By immunochemical assays, it is shown that these receptors are expressed in both the neuronal cell body and the proximal dendrites. Colocalization of A(1)Rs with microtubule-associated protein 2 and cell surface adenosine deaminase was shown by confocal microscopy. The high degree of colocalization observed between A(1)Rs and ectoadenosine deaminase in neurons could suggest an important role of the enzyme in adenosine-mediated neuromodulation. 相似文献
16.
17.
Hensley K Floyd RA Gordon B Mou S Pye QN Stewart C West M Williamson K 《Journal of neurochemistry》2002,82(2):365-374
Familial amyotrophic lateral sclerosis (FALS) is often caused by gain-of-function mutations in Cu,Zn-superoxide dismutase (SOD1). Multiprobe ribonuclease protection assays (RPAs) were used to investigate expression of 36 different cytokines and apoptosis-related genes in spinal cords of mice that ubiquitously express human SOD1 bearing a glycine (r) alanine substitution at residue 93 (G93A-SOD1). Mice were studied at late presymptomatic stage (80 days), and at 120 days when the animals experience severe hindlimb paralysis and accumulation of oxidatively modified proteins. Spinal cord tissue from G93A-SOD1 mice expressed a selective subset of macrophage-typical cytokines (monokines) including interleukin (IL)1alpha, IL1beta and IL1RA at 80 days increasing by 120 days. Contrastingly, T-cell derived cytokines (lymphokines) including IL2, IL3 and IL4 were detected at low levels in non-transgenic mice but these were not elevated in G93A-SOD1 mice even at 120 days. Apoptosis-related genes were generally unaffected at 80 days but multiple caspases and death receptor components were up-regulated at 120 days; the only exceptions being FADD and the tumor necrosis factor (TNF)alpha receptor p55 which was up-regulated at 80 days and increased further at 120 days. These data indicate that in the G93A-SOD1 mouse: (i) cytokine expression changes precede bulk protein oxidation and apoptosis gene expression; (ii) lymphocyte contributions to cytokine expression in FALS are likely minor; and (iii) TNFalpha and its receptors may link inflammation to apoptosis in ALS. 相似文献
18.
Proteomic analysis of spinal cord of presymptomatic amyotrophic lateral sclerosis G93A SOD1 mouse 总被引:1,自引:0,他引:1
Massignan T Casoni F Basso M Stefanazzi P Biasini E Tortarolo M Salmona M Gianazza E Bendotti C Bonetto V 《Biochemical and biophysical research communications》2007,353(3):719-725
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, whose primary mechanisms or causes are still not defined and for which no effective treatment is available. We have recently reported that before disease onset the level of tyrosine nitrated proteins is increased in the G93A SOD1 transgenic mouse model of ALS. In the present investigation, we carried out a proteomic analysis of spinal cord extracts from G93A SOD1 mice at the presymptomatic stage of the disease to further unravel primary events in the pathogenesis and tentatively screen for potential pharmacological targets. Using a robust two-dimensional gel electrophoresis-based proteomic approach, we detected a number of proteins differentially represented in presymptomatic mice in comparison with controls. Alterations of these proteins correlate with mitochondrial dysfunction, aggregation, and stress response. Moreover, we found a variation in the isoform pattern of cyclophilin A, a molecular chaperone that protects cells from the oxidative stress. 相似文献
19.
Thompson M Marecki JC Marinesco S Labrie V Roder JC Barger SW Crow JP 《Journal of neurochemistry》2012,120(4):598-610
D-serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of D-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of D-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by D-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades D-serine as well. D-serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice--the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of D-serine to ALS mice dramatically lowers cord levels of D-serine, leading to changes in the onset and survival very similar to SR deletion. D-serine treatment also increases cord levels of the alanine-serine-cysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases D-serine is not known, these results strongly suggest that SR and D-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator. 相似文献
20.
Intracerebroventricular administration of Cystatin C ameliorates disease in SOD1‐linked amyotrophic lateral sclerosis mice 下载免费PDF全文
Seiji Watanabe Okiru Komine Fumito Endo Keisuke Wakasugi Koji Yamanaka 《Journal of neurochemistry》2018,145(1):80-89
Cystatin C (CysC) is a major protein component of Bunina bodies, which are a pathological hallmark observed in the remaining motor neurons of patients with amyotrophic lateral sclerosis (ALS). Dominant mutations in the SOD1 gene, encoding Cu/Zn superoxide dismutase (SOD1), are causative for a subset of inherited ALS cases. Our previous study showed that CysC exerts a neuroprotective effect against mutant SOD1‐mediated toxicity in vitro; however, in vivo evidence of the beneficial effects mediated by CysC remains obscure. Here we examined the therapeutic potential of recombinant human CysC in vivo using a mouse model of ALS in which the ALS‐linked mutated SOD1 gene is expressed (SOD1G93A mice). Intracerebroventricular administration of CysC during the early symptomatic SOD1G93A mice extended their survival times. Administered CysC was predominantly distributed in ventral horn neurons including motor neurons, and induced autophagy through AMP‐activated kinase activation to reduce the amount of insoluble mutant SOD1 species. Moreover, PGC‐1α, a disease modifier of ALS, was restored by CysC through AMP‐activated kinase activation. Finally, the administration of CysC also promoted aggregation of CysC in motor neurons, which is similar to Bunina bodies. Taken together, our findings suggest that CysC represents a promising therapeutic candidate for ALS.