Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We searched for the presence of apoptotic cell death and studied the distribution of bcl-2, an oncoprotein that counteracts apoptosis, in amyotrophic lateral sclerosis (ALS). Brain and spinal cord specimens from 12 ALS patients were compared with those from six non-neurological controls. ALS brain tissue was pre-selected by the presence of reactive cortical damage. Apoptosis was demonstrated by in situ end-labelling of fragmented DNA, a method that is suitable for formalin-fixed, paraffin-embedded tissue. All ALS patients exhibited some apoptosis, eight of them did so in each of the three central nervous system (CNS)-levels studied. Apoptosis was not restricted to the motor system, but also affected other neuronal and non-neuronal CNS elements. Apoptosis corresponded with cell shrinkage, and neuronophagia in Nissl stains and with small Nissl-positive bodies. None of the non-neurological controls showed as much apoptosis as any of the ALS cases. Immunocytochemically, the overall distribution of Bcl-2 did not differ between ALS and non-neurological controls. In ALS, however, we found variable degrees of increased Bcl-2 expressed in the nuclei and in the cytoplasm. We found no inverse relationship between apoptosis and bcl-2 expression.
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PMID:Apoptosis in amyotrophic lateral sclerosis is not restricted to motor neurons. Bcl-2 expression is increased in unaffected post-central gyrus. 874 39

One of the primary neurodegenerative events occurring in amyotrophic lateral sclerosis (ALS) is the selective loss of spinal cord alpha motor neurons. To study the potential role of apoptosis in the degeneration of these motor neurons, in situ hybridization was used to measure the expression of two apoptotic cell death genes, bcl-2 and bax, in control and ALS lumbar spinal cord sections. The strongest hybridization signal for bcl-2 mRNA in neurological and nonneurological control spinal cords was found primarily in lamina IX alpha motor neurons, while a weaker hybridization signal was found in neurons of Clarke's nucleus and the proper sensory nucleus of the dorsal horn. Surviving lamina IX motor neurons in ALS spinal cord sections also expressed bcl-2 mRNA, but at levels that were significantly and selectively decreased (4.7-fold) compared with controls. bax mRNA hybridization signal was detected in several cells throughout the gray matter in control and ALS lumbar spinal cord, but was significantly and selectively increased (2.8-fold) in ALS motor neurons. Given the proposed interactive roles of these genes in apoptosis, the present findings favor a scenario in which this mode of cell death would contribute to spinal cord motor neuron degeneration in ALS.
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PMID:Altered expression of bcl-2 and bax mRNA in amyotrophic lateral sclerosis spinal cord motor neurons. 879 27

Mutations in the gene encoding copper/zinc superoxide dismutase enzyme produce an animal model of familial amyotrophic lateral sclerosis (FALS), a fatal disorder characterized by paralysis. Overexpression of the proto-oncogene bcl-2 delayed onset of motor neuron disease and prolonged survival in transgenic mice expressing the FALS-linked mutation in which glycine is substituted by alanine at position 93. It did not, however, alter the duration of the disease. Overexpression of bcl-2 also attenuated the magnitude of spinal cord motor neuron degeneration in the FALS-transgenic mice.
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PMID:Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. 922 5

Apoptosis has been described as one of the mechanisms of muscle fiber loss in infantile spinal muscular atrophy. In order to investigate if muscle fiber-apoptosis plays a role in other denervating disorders as well, we studied DNA-fragmentation, a hallmark of apoptosis, by the TUNEL-method and, moreover, the expression patterns of apoptosis-related proteins in 2 patients suffering from ALS and in 6 patients with polyneuropathy. We identified DNA-cleavage in muscle fibers of all these patients. Furthermore, we found strong expression of bax and ICE promoting apoptosis in muscle fibers. However, also strong expression of the anti-apoptotic factor bcl-2 was found. Our findings indicate that defective innervation may prompt muscle fibers to activate an intrinsic "suicide" programme which is promoted by the proapoptotic factors bax and ICE, which seems to induce formation of apoptotic bodies by cleavage of actin. Nevertheless, there are also anti-apoptotic strategies in muscle fibers manifested by expression of the bax-antagonist bcl-2 which is able to neutralize high bax levels.
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PMID:DNA-fragmentation and apoptosis-related proteins of muscle cells in motor neuron disorders. 944 76

CuZn superoxide dismutase (CuZn SOD) is one of several antioxidant enzymes that defend the cell against damage by oxygen free radicals. Mutations of the SOD1 gene encoding CuZn SOD are found in patients with familial amyotrophic lateral sclerosis (FALS), a progressive and fatal paralytic disease that is caused by the death of motor neurons in cortex, brainstem and spinal cord. The disease can be reproduced in transgenic mice by expression of mutant human CuZn SOD. Recent studies both in vitro and in vivo suggest that the effect of mutation is to enhance the generation of oxygen radicals by the mutant enzyme. Thus, mutation converts a protective, antioxidant enzyme into a destructive, prooxidant form that catalyses free radical damage to which motor neurons are selectively vulnerable. Recent studies of neuroprotective agents in the FALS model show that inhibition of oxidative mechanisms (copper chelation therapy, dietary antioxidants, and coexpression of bcl-2) delays disease onset but does not extend disease duration. In contrast, inhibition of glutamatergic or apoptotic mechanisms (riluzole, gabapentin, and coexpression of glutamatergic or apoptotic mechanisms (riluzole, gabapentin, and coexpression of an inhibitor of caspase-1) has no effect on disease onset but extends survival by increasing the duration of symptomatic disease. Thus, neuroprotective agents differentially target the processes underlying disease initiation and propagation.
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PMID:Mutant CuZn superoxide dismutase in motor neuron disease. 972 38

There is mounting evidence for mitochondrial involvement in neurodegenerative diseases including Alzheimer's and Parkinson's disease and amyotrophic lateral sclerosis. Mitochondrial DNA mutations, whether inherited or acquired, lead to impaired electron transport chain (ETC) functioning. Impaired electron transport, in turn, leads to decreased ATP production, formation of damaging free-radicals, and altered calcium handling. These toxic consequences of ETC dysfunction lead to further mitochondrial damage including oxidation of mitochondrial DNA, proteins, and lipids, and opening of the mitochondrial permeability transition pore, an event linked to cell death in numerous model systems. Although protective nuclear responses such as antioxidant enzymes and bcl-2 may be induced to combat these pathological changes, such a vicious cycle of increasing oxidative damage may insidiously damage neurons over a period of years, eventually leading to neuronal cell death. This hypothesis, a synthesis of the mitochondrial mutations and oxidative stress hypotheses of neurodegeneration, is readily tested experimentally, and clearly points out many potential therapeutic targets for preventing or ameliorating these diseases.
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PMID:An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. 997 49

Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) underlie some familial cases of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by loss of cortical, brainstem and spinal motoneurons. Transgenic mice over- expressing a mutated form of human SOD1 containing a Gly-->Ala substitution at position 93 (SOD1(G93A)) develop a severe, progressive motoneuron disease. We investigated the potential of recombinant adeno-associated virus (rAAV) to transfer neuroprotective molecules in this animal ALS model. Initial experiments showed that injection of an rAAV vector encoding green fluorescent protein unilaterally into the lumbar spinal cord of wild-type mice leads to expression of the reporter gene in 34.7 +/- 5.2% of the motoneurons surrounding the injection site. Intraspinal injection of an rAAV encoding the anti-apoptotic protein bcl-2 in SOD1 (G93A) mice resulted in sustained bcl-2 expression in motoneurons and significantly increased the number of surviving motoneurons at the end-stage of disease. Moreover, the compound muscle action potential amplitude elicited by nerve stimulation and recorded by electromyographic measurements was higher in the rAAV-bcl-2-treated group than in controls. Local bcl-2 expression in spinal motoneurons delayed the appearance of signs of motor deficiency but was not sufficient to prolong the survival of SOD1 (G93A) mice. To our know-ledge, this study describes the first successful transduction and protection of spinal motoneurons by direct gene transfer in a model of progressive motoneuron disease. Our results support the use of AAVs for the delivery of protective genes to spinal cord moto-neurons as a possible way to enhance motoneuron survival and repair.
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PMID:Increased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bcl-2. 1074 88

There are several incurable diseases of motor neuron degeneration, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, hereditary spastic hemiplegia, spinal muscular atrophy, and bulbospinal atrophy. Advances in gene transfer techniques coupled with new insights into molecular pathology have opened promising avenues for gene therapy aimed at halting disease progression. Nonviral preparations and recombinant adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses may ultimately transduce sufficient numbers of cerebral, brainstem, and spinal cord neurons for therapeutic applications. This could be accomplished by direct injection, transduction of lower motor neurons via retrograde transport after intramuscular injection, or cell-based therapies. Studies using transgenic mice expressing mutant superoxide dismutase 1 (SOD1), a model for one form of ALS, established that several proteins were neuroprotective, including calbindin, bcl-2, and growth factors. These same molecules promoted neuronal survival in other injury models, suggesting general applicability to all forms of ALS. Potentially correctable genetic lesions have also been identified for hereditary spastic hemiplegia, bulbospinal atrophy, and spinal muscular atrophy. Finally, it may be possible to repopulate lost corticospinal and lower motor neurons by transplanting stem cells or stimulating native progenitor populations. The challenge ahead is to translate these basic science breakthroughs into workable clinical practice.
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PMID:Gene therapy for amyotrophic lateral sclerosis and other motor neuron diseases. 1109 37

Amytrophic lateral sclerosis is characterized by relentlessly progressive degeneration of spinal cord motor neurons. During the disease, the bcl-2 family genes have been reported to alter their expression levels. To understand the meaning of these changes, the expression pattern of Bax in rat spinal cord and its changing pattern during normal aging were investigated by immunohistochemical staining. Spatial expression of the protein showed a diffuse distribution pattern with immunoreactivity more prominent in the anterior hom. With advancement of age, the cell densities of Bax-positive cells tended to increase. The increasing expression of Bax might be positively associated with amyotrophic lateral sclerosis. This work demonstrates for the first time how Bax expression changes in rat spinal cord during normal aging.
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PMID:Spatial and temporal distribution of Bax in rat spinal cord during normal aging. 1121 Apr 37

To investigate disease-related differences of cell death and apoptosis in human denervation atrophy, we studied DNA fragmentation by the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) method in 38 biopsies of clinically nonaffected and affected muscles from patients with sporadic amyotrophic lateral sclerosis (sALS), in 13 muscle biopsies from patients with chronic peripheral neuropathies, and in 8 biopsies from control subjects. In addition, expression of apoptosis-related proteins, bax, bcl-2, and Fas, was studied in 20 biopsies of sALS and 10 chronic peripheral neuropathies. We identified DNA cleavage in 10% of myofibers of patients and in up to 1.5% of control samples. In clinically affected muscles of ALS, a larger amount of TUNEL-positive myofibers (mean 10.5 +/- 5.9%) was detected, similar to chronic peripheral neuropathies (mean 10.0 +/- 7.4%). Atrophic myofibers were immunopositive for bax, bcl-2, and, to a weaker extent, for Fas. However, bax-, bcl-2-, or Fas-positive atrophic myofibers did not reveal consecutive DNA cleavage. Differences between sALS subgroups and chronic peripheral neuropathies were not found. In human denervation atrophy the bcl-2/bax and the FasL/Fas systems are apparently active independently of DNA fragmentation and apoptosis. DNA fragmentation thus displays an additional reaction that is not disease-specific at chronic stages of human denervation processes, probably recapitulating events like skeletal muscle fiber remodeling in embryonic skeletal tissue development.
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PMID:Cell death and apoptosis-related proteins in muscle biopsies of sporadic amyotrophic lateral sclerosis and polyneuropathy. 1143 85


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