共查询到20条相似文献,搜索用时 342 毫秒
1.
Vinod Sundaramoorthy Adam K. Walker Justin Yerbury Kai Ying Soo Manal A. Farg Vy Hoang Rafaa Zeineddine Damian Spencer Julie D. Atkin 《Cellular and molecular life sciences : CMLS》2013,70(21):4181-4195
Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of ALS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. ALS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. However, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of ALS pathology. Similarly, whilst dysfunction to the ER–Golgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial ALS, it remains unclear whether misfolded, wildtype SOD1 triggers ER–Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. Hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the ER–Golgi apparatus, leading to Golgi fragmentation, induction of ER stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces ER–Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. Hence extracellular misfolded wildtype or mutant SOD1 induce dysfunction to ER–Golgi compartments characteristic of ALS in neuronal cells, implicating extracellular SOD1 in the spread of pathology among motor neurons in both sporadic and familial ALS. 相似文献
2.
Anika M. Helferich Sarah J. Brockmann Jörg Reinders Dhruva Deshpande Karlheinz Holzmann David Brenner Peter M. Andersen Susanne Petri Dietmar R. Thal Jens Michaelis Markus Otto Steffen Just Albert C. Ludolph Karin M. Danzer Axel Freischmidt Jochen H. Weishaupt 《Cellular and molecular life sciences : CMLS》2018,75(23):4301-4319
3.
Research advances in gene therapy approaches for the treatment of amyotrophic lateral sclerosis 总被引:1,自引:1,他引:0
Nizzardo M Simone C Falcone M Riboldi G Rizzo F Magri F Bresolin N Comi GP Corti S 《Cellular and molecular life sciences : CMLS》2012,69(10):1641-1650
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons that causes progressive muscle
weakness, paralysis, and premature death. No effective therapy is available. Research in the motor neuron field continues
to grow, and recent breakthroughs have demonstrated the possibility of completely achieving rescue in animal models of spinal
muscular atrophy, a genetic motor neuron disease. With adeno-associated virus (AAV) vectors, gene transfer can be achieved
with systemic non-invasive injection and minimal toxicity. In the context of this success, we review gene therapy approaches
for ALS, considering what has been done and the possible future directions for effective application of the latest generation
of vectors for clinical translation. We focus on recent developments in the areas of RNA/antisense-mediated silencing of specific
ALS causative genes like superoxide dismutase-1 and other molecular pathogenetic targets, as well as the administration of
neuroprotective factors with viral vectors. We argue that gene therapy offers new opportunities to open the path for clinical
progress in treating ALS. 相似文献
4.
Federica Rizzo Giulietta Riboldi Sabrina Salani Monica Nizzardo Chiara Simone Stefania Corti Eva Hedlund 《Cellular and molecular life sciences : CMLS》2014,71(6):999-1015
Neurodegenerative disorders are characterized by the selective vulnerability and progressive loss of discrete neuronal populations. Non-neuronal cells appear to significantly contribute to neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS), Parkinson, and Alzheimer’s disease. In ALS, there is deterioration of motor neurons in the cortex, brainstem, and spinal cord, which control voluntary muscle groups. This results in muscle wasting, paralysis, and death. Neuroinflammation, characterized by the appearance of reactive astrocytes and microglia as well as macrophage and T-lymphocyte infiltration, appears to be highly involved in the disease pathogenesis, highlighting the involvement of non-neuronal cells in neurodegeneration. There appears to be cross-talk between motor neurons, astrocytes, and immune cells, including microglia and T-lymphocytes, which are subsequently activated. Currently, effective therapies for ALS are lacking; however, the non-cell autonomous nature of ALS may indicate potential therapeutic targets. Here, we review the mechanisms of action of astrocytes, microglia, and T-lymphocytes in the nervous system in health and during the pathogenesis of ALS. We also evaluate the therapeutic potential of these cellular populations, after transplantation into ALS patients and animal models of the disease, in modulating the environment surrounding motor neurons from pro-inflammatory to neuroprotective. We also thoroughly discuss the recent advances made in the field and caveats that need to be overcome for clinical translation of cell therapies aimed at modulating non-cell autonomous events to preserve remaining motor neurons in patients. 相似文献
5.
Positive (adaptive) selection has recently been implied in human superoxide dismutase 1 (SOD1), a highly abundant antioxidant protein with energy signaling and antiaging functions, one of very few examples of direct selection on a human protein product (exon); the molecular drivers of this selection are unknown. We mapped 30 extant SOD1 sequences to the recently established mammalian species tree and inferred ancestors, key substitutions, and signatures of selection during the protein’s evolution. We detected elevated substitution rates leading to great apes (Hominidae) at ~1 per 2 million years, significantly higher than in other primates and rodents, although these paradoxically generally evolve much faster. The high evolutionary rate was partly due to relaxation of some selection pressures and partly to distinct positive selection of SOD1 in great apes. We then show that higher stability and net charge and changes at the dimer interface were selectively introduced upon separation from old world monkeys and lesser apes (gibbons). Consequently, human, chimpanzee and gorilla SOD1s have a net charge of ?6 at physiological pH, whereas the closely related gibbons and macaques have ?3. These features consistently point towards selection against the malicious aggregation effects of elevated SOD1 levels in long-living great apes. The findings mirror the impact of human SOD1 mutations that reduce net charge and/or stability and cause ALS, a motor neuron disease characterized by oxidative stress and SOD1 aggregates and triggered by aging. Our study thus marks an example of direct selection for a particular chemical phenotype (high net charge and stability) in a single human protein with possible implications for the evolution of aging. 相似文献
6.
Irene Faravelli Giulietta Riboldi Monica Nizzardo Chiara Simone Chiara Zanetta Nereo Bresolin Giacomo P. Comi Stefania Corti 《Cellular and molecular life sciences : CMLS》2014,71(17):3257-3268
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by degeneration of upper and lower motor neurons. There are currently no clinically impactful treatments for this disorder. Death occurs 3–5 years after diagnosis, usually due to respiratory failure. ALS pathogenesis seems to involve several pathological mechanisms (i.e., oxidative stress, inflammation, and loss of the glial neurotrophic support, glutamate toxicity) with different contributions from environmental and genetic factors. This multifaceted combination highlights the concept that an effective therapeutic approach should counteract simultaneously different aspects: stem cell therapies are able to maintain or rescue motor neuron function and modulate toxicity in the central nervous system (CNS) at the same time, eventually representing the most comprehensive therapeutic approach for ALS. To achieve an effective cell-mediated therapy suitable for clinical applications, several issues must be addressed, including the identification of the most performing cell source, a feasible administration protocol, and the definition of therapeutic mechanisms. The method of cell delivery represents a major issue in developing cell-mediated approaches since the cells, to be effective, need to be spread across the CNS, targeting both lower and upper motor neurons. On the other hand, there is the need to define a strategy that could provide a whole distribution without being too invasive or burdened by side effects. Here, we review the recent advances regarding the therapeutic potential of stem cells for ALS with a focus on the minimally invasive strategies that could facilitate an extensive translation to their clinical application. 相似文献
7.
Rachna S. Pandya Haining Zhu Wei Li Robert Bowser Robert M. Friedlander Xin Wang 《Cellular and molecular life sciences : CMLS》2013,70(24):4729-4745
Amyotrophic lateral sclerosis (ALS) is a fatal chronic neurodegenerative disease whose hallmark is proteinaceous, ubiquitinated, cytoplasmic inclusions in motor neurons and surrounding cells. Multiple mechanisms proposed as responsible for ALS pathogenesis include dysfunction of protein degradation, glutamate excitotoxicity, mitochondrial dysfunction, apoptosis, oxidative stress, and inflammation. It is therefore essential to gain a better understanding of the underlying disease etiology and search for neuroprotective agents that might delay disease onset, slow progression, prolong survival, and ultimately reduce the burden of disease. Because riluzole, the only Food and Drug Administration (FDA)-approved treatment, prolongs the ALS patient’s life by only 3 months, new therapeutic agents are urgently needed. In this review, we focus on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discuss their impact on disease progression. 相似文献
8.
Free amino acids were estimated quantitatively in the motor cortex from 3 patients with amyotrophic lateral sclerosis (ALS) and 11 control subjects. Among 7 amino acids which showed statistically significant changes, taurine was the only one which was increased constantly and most markedly in the motor cortex of all the 3 ALS cases. It was suggested that the metabolism of sulfur amino acids might be affected in comparatively early stages of ALS. 相似文献
9.
Summary The pronormoblasts and normoblasts in Swiss albino mice were found to be very sensitive to radiation and their percentage was reduced drastically after exposure to gamma-rays. The degree of damage increased with increase in radiation dose. MPG reduced the initial damage and brought about an early and fast recovery. It is concluded that the drug protects the stem cells and thereby reduces the depletion of the regenerating pool which causes a more efficient and accelerated recovery. 相似文献
10.
Serotonin metabolism in the CNS in cerebellar ataxic mice 总被引:2,自引:0,他引:2
The metabolism of 5-hydroxytryptamine (5-HT) in the CNS was investigated in four kinds of morphologically different ataxic mice; reeler, staggerer, weaver and Purkinje cell degeneration mutants, and in hypocerebellar mice experimentally produced by injection of cytosine arabinoside. 5-HT and 5-hydroxyidoleacetic acid concentrations and tryptophan hydroxylase (TrpOH) activity were measured in the cerebrum, cerebellum and brain stem, respectively. TrpOH activity was significantly reduced only in the reeler mouse. The enhancements of the cerebellar 5-HT metabolism observed in the ataxic mice other than the reeler were supposed to be pseudo-enhancements subsequent to the cerebellar hypoplasia. 相似文献
11.
Steinbeck JA Koch P Derouiche A Brüstle O 《Cellular and molecular life sciences : CMLS》2012,69(3):461-470
While the availability of pluripotent stem cells has opened new prospects for generating neural donor cells for nervous system
repair, their capability to integrate with adult brain tissue in a structurally relevant way is still largely unresolved.
We addressed the potential of human embryonic stem cell-derived long-term self-renewing neuroepithelial stem cells (lt-NES
cells) to establish axonal projections after transplantation into the adult rodent brain. Transgenic and species-specific
markers were used to trace the innervation pattern established by transplants in the hippocampus and motor cortex. In vitro,
lt-NES cells formed a complex axonal network within several weeks after the initiation of differentiation and expressed a
composition of surface receptors known to be instrumental in axonal growth and pathfinding. In vivo, these donor cells adopted
projection patterns closely mimicking endogenous projections in two different regions of the adult rodent brain. Hippocampal
grafts placed in the dentate gyrus projected to both the ipsilateral and contralateral pyramidal cell layers, while axons
of donor neurons placed in the motor cortex extended via the external and internal capsule into the cervical spinal cord and
via the corpus callosum into the contralateral cortex. Interestingly, acquisition of these region-specific projection profiles
was not correlated with the adoption of a regional phenotype. Upon reaching their destination, human axons established ultrastructural
correlates of synaptic connections with host neurons. Together, these data indicate that neurons derived from human pluripotent
stem cells are endowed with a remarkable potential to establish orthotopic long-range projections in the adult mammalian brain. 相似文献
12.
Summary Free amino acids were estimated quantitatively in the motor cortex from 3 patients with amyotrophic lateral sclerosis (ALS) and 11 control subjects. Among 7 amino acids which showed statistically significant changes, taurine was the only one which was increased constantly and most markedly in the motor cortex of all the 3 ALS cases. It was suggested that the metabolism of sulfur amino acids might be affected in comparatively early stages of ALS.Acknowledgments. The authors are grateful to Dr M. Uono, Department of Neurology, Tokyo Metropolitan Hospital of Fuchu, and Dr K. Hirayama, Department of Neurology, Brain Research Institute, School of Medicine, Chiba University, for their generous cooperation. 相似文献
13.
Summary 1. In mice,reserpine (5 mg/kg) causes a long-lasting depletion of the brain for -aminobutyric acid (GABA), which corresponds temporally to the lowered seizure threshold (electroshock).2.Iproniazid prohibits both the depletion of GABA and the lowering of seizure threshold.3. Relations between amine- and GABA-metabolism of the brain are pointed out. 相似文献
14.
Intraperitoneal injections of cysteine or N-acetyl cysteine induce a depletion of reduced glutathione (GSH) in rat brain. The doses required to promote GSH depletion are lower than those reported to cause a disseminate neurodegenerative syndrome. Since physiological GSH concentrations are required to maintain cell membranes, we suggest that consideration of the cysteine-induced GSH depletion is important in attempts to understand the mechanism of cysteine-induced cytotoxicity in brain. 相似文献
15.
E. C. Frederick M. F. Hamant S. A. Rasmussen A. K. Chan G. E. Goslow Jr 《Cellular and molecular life sciences : CMLS》1978,34(3):372-374
Summary Single motor units in striped skunk medial gastrocnemias were isolated and physiologically characterized. Individual muscle unit fibres tagged by glycogen depletion were analyzed histochemically and found to have histochemical profiles consistently correlated with the physiological findings.This work was supported by the Organized Research Committee, Northern Arizona University. 相似文献
16.
Calcitonin gene related peptide stimulates adenylate cyclase activity in rat striated muscle 总被引:4,自引:0,他引:4
H Kobayashi K Hashimoto S Uchida J Sakuma K Takami M Tohyama F Izumi H Yoshida 《Experientia》1987,43(3):314-316
Rat calcitonin gene related peptide (CGRP) and salmon calcitonin (CT) stimulated adenylate cyclase activity in a dose-dependent manner in the rat diaphragm and in the kidney. The ED50 value of rat CGRP was lower and that of salmon CT was higher in the diaphragm than in the kidney. These results suggest that CGRP stimulates adenylate cyclase activity in the striated muscle by reacting with sites distinct from the site in the kidney. 相似文献
17.
Chiara F. Valori Liliana Brambilla Francesca Martorana Daniela Rossi 《Cellular and molecular life sciences : CMLS》2014,71(2):287-297
Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia–neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS. 相似文献
18.
H. Kobayashi K. Hashimoto S. Uchida J. Sakuma K. Takami M. Tohyama F. Izumi H. Yoshida 《Cellular and molecular life sciences : CMLS》1987,43(3):314-316
Summary Rat calcitonin gene related peptide (CGRP) and salmon calcitonin (CT) stimulated adenylate cyclase activity in a dose-dependent manner in the rat diaphragm and in the kidney. The ED50 value of rat CGRP was lower and that of salmon CT was higher in the diaphragm than in the kidney. These results suggest that CGRP stimulates adenylate cyclase activity in the striated muscle by reacting with sites distinct from the site in the kidney. 相似文献
19.
Deacon JC Bloemink MJ Rezavandi H Geeves MA Leinwand LA 《Cellular and molecular life sciences : CMLS》2012,69(13):2261-2277
The myosin isoform composition of the heart is dynamic in health and disease and has been shown to affect contractile velocity and force generation. While different mammalian species express different proportions of α and β myosin heavy chain, healthy human heart ventricles express these isoforms in a ratio of about 1:9 (α:β) while failing human ventricles express no detectable α-myosin. We report here fast-kinetic analysis of recombinant human α and β myosin heavy chain motor domains. This represents the first such analysis of any human muscle myosin motor and the first of α-myosin from any species. Our findings reveal substantial isoform differences in individual kinetic parameters, overall contractile character, and predicted cycle times. For these parameters, α-subfragment 1 (S1) is far more similar to adult fast skeletal muscle myosin isoforms than to the slow β isoform despite 91% sequence identity between the motor domains of α- and β-myosin. Among the features that differentiate α- from β-S1: the ATP hydrolysis step of α-S1 is ~ten-fold faster than β-S1, α-S1 exhibits ~five-fold weaker actin affinity than β-S1, and actin·α-S1 exhibits rapid ADP release, which is >ten-fold faster than ADP release for β-S1. Overall, the cycle times are ten-fold faster for α-S1 but the portion of time each myosin spends tightly bound to actin (the duty ratio) is similar. Sequence analysis points to regions that might underlie the basis for this finding. 相似文献
20.
John C. Deacon Marieke J. Bloemink Heresh Rezavandi Michael A. Geeves Leslie A. Leinwand 《Cellular and molecular life sciences : CMLS》2012,69(24):4239-4255
The myosin isoform composition of the heart is dynamic in health and disease and has been shown to affect contractile velocity and force generation. While different mammalian species express different proportions of α and β myosin heavy chain, healthy human heart ventricles express these isoforms in a ratio of about 1:9 (α:β) while failing human ventricles express no detectable α-myosin. We report here fast-kinetic analysis of recombinant human α and β myosin heavy chain motor domains. This represents the first such analysis of any human muscle myosin motor and the first of α-myosin from any species. Our findings reveal substantial isoform differences in individual kinetic parameters, overall contractile character, and predicted cycle times. For these parameters, α-subfragment 1 (S1) is far more similar to adult fast skeletal muscle myosin isoforms than to the slow β isoform despite 91% sequence identity between the motor domains of α- and β-myosin. Among the features that differentiate α- from β-S1: the ATP hydrolysis step of α-S1 is ~ten-fold faster than β-S1, α-S1 exhibits ~five-fold weaker actin affinity than β-S1, and actin·α-S1 exhibits rapid ADP release, which is >ten-fold faster than ADP release for β-S1. Overall, the cycle times are ten-fold faster for α-S1 but the portion of time each myosin spends tightly bound to actin (the duty ratio) is similar. Sequence analysis points to regions that might underlie the basis for this finding. 相似文献