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)

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons, characterized by depositions of neurofilaments in the perikarya and proximal axons. The pathogenesis of ALS remains poorly understood, but two lines of evidence suggest that neurofilament accumulation may play a causal role. First, transgenic mice that overexpress neurofilament proteins show motor neuron degeneration and, second, variant alleles of the neurofilament heavy-subunit gene (NF-H) have been found in some human ALS patients. To investigate how disorganized neurofilaments might cause neurodegeneration, we examined axonal transport of newly synthesized proteins in mice that overexpress the human NF-H gene. We observed dramatic defects of axonal transport, not only of neurofilament proteins but also of other proteins, including tubulin and actin. Ultrastructural analysis revealed a paucity of cytoskeletal elements, smooth endoplasmic reticulum and especially mitochondria in the degenerating axons. We therefore propose that the neurofilament accumulations observed in these mice cause axonal degeneration by impeding the transport of components required for axonal maintenance, and that a similar mechanism may account for the pathogenesis of ALS in human patients.
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PMID:Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis. 753 96

Antibodies to Ca channels in ALS patients IgG can be demonstrated to enhance Ca current and cause cell injury and death in a motoneuron cell line in vitro. To determine whether these antibodies can alter neuronal calcium homeostasis in vivo IgG fractions from six ALS patients were injected intraperitoneally into mice, and neurons assayed by ultrastructural techniques for calcium content. After 24 h, all six ALS IgG by (40 mg/animal) increased vesicle number in spinal motoneuron axon terminals, and in boutons synapsing on spinal motoneurons. Using the oxalate-pyroantimonate technique for calcium precipitation, these antibodies produced dose-dependent calcium increases either in axon terminal synaptic vesicles and mitochondria, or in rough endoplasmic reticulum, mitochondria, and Golgi complex of spinal motoneuron and frontal cortex pyramidal cells. ALS IgG was itself internalized and also induced neurofilament H phosphorylation. The observed changes in ultrastructure and calcium compartmentation were restricted to motoneurons; normal and disease control IgG, which did not possess antibodies enhancing calcium entry, did not exert similar effects. These data demonstrate that ALS IgG containing Ca-channel antibodies can alter calcium homeostasis of motoneurons in vivo.
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PMID:Antibodies to calcium channels from ALS patients passively transferred to mice selectively increase intracellular calcium and induce ultrastructural changes in motoneurons. 757 Mar 50

Clinico-environmental and pathological variables were obtained from 10 patients with amyotrophic lateral sclerosis using particle-induced X-ray emission spectrometry (PIXE) and morphometric-statistical analysis. Statistical analysis identified a model that maximally predicts the Bb% (frequency of Bunina bodies) from a selected set, four variables: (1) nucleolar index, (2) magnesium (Mg) content, (3) aluminum (Al) content, and (4) duration of illness. Among them, only the Al content proved important. To determine their chemical nature, electron energy loss spectrometry (EELS) was applied at the ultrastructural level; it revealed that within the motor neuron, Al strongly binds to the Bunina body as well as rough endoplasmic reticulum (rER), and lesser strongly to mitochondria and lipofuscin granule. Thus, it is chemically similar to the rER, providing preferential binding sites to aluminum. The Bunina bodies may be an end-product of the nucleic acid dysmetabolism at rER caused by Al along with Mg depletion.
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PMID:Bunina body formation in amyotrophic lateral sclerosis: a morphometric-statistical and trace element study featuring aluminum. 765 May 36

Transgenic mice expressing mutant Cu,Zn superoxide dismutase (SOD), containing a substitution of glycine at position 93 by alanine, develop disease prevalently affecting motor neurons. Light microscopical and ultrastructural studies reveal that the earliest pathological features are microvesiculation of large neurons of the anterior horns of the spinal cord. These vacuoles originate from dilation of rough endoplasmic reticulum and from degenerating mitochondria. At the end stage of the disease, the microvesicular pattern gives way to atrophic anterior horns showing severe neuronal depletion and hyaline, filamentous inclusions in some of the surviving neurons. Posterior horn neurons and dorsal root ganglia are not affected. With disease progression, moderate degeneration of anterior and lateral columns, severe degeneration of anterior roots, and mild degeneration in posterior columns and roots become apparent. This study shows that a mutation in SOD, known to occur in a percentage of familial amyotrophic lateral sclerosis patients, may affect only selective neuronal populations, although SOD is a ubiquitous enzyme.
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PMID:Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. 799 31

Environmental factors, particularly chronic exposure to aluminum (Al) and manganese (Mn) with dietary deficiency of calcium (Ca) and magnesium (Mg), are speculated to be contributory in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, the mechanisms by which these elements accumulate in the CNS tissues and induce neuronal death are not known. In the present study, we investigated the retrograde transport of Al as a possible mechanism of pathogenesis. Al (as aluminum chloride or maltol) was injected into the subepineurial space of the sciatic nerve with subsequent morphological evaluation of the neurotoxic effect on spinal motor neurons in rabbits. Spheroid/globules, central and peripheral chromatolysis, and neuronal degeneration were observed in the spinal anterior horn in Al-maltol, Al chloride, and maltol treated rabbits to more marked extent than those in uninjected or saline controls. By electron microscopy, the soma and dendrites of neurons in the anterior horn at the fifth lumbar spinal cord in the Al-treated rabbit showed marked edematous change, fragmentation of granular endoplasmic reticulum, increased accumulation of neurofilament, and accumulation of free ribosomes and lipid-droplet-like structures. Horseradish peroxidase (HRP) reactive product was seen in the axons and cytoplasm of Schwann cells of the sciatic nerve in Al-maltol treated rabbits, suggesting that the permeability of the blood-nerve-barrier was increased by injection of Al-maltol. We suggest that Al, subperineurially injected, was absorbed into the spinal cord and induced degeneration of spinal motor neurons in these rabbits. These findings indicate that the retrograde transport of Al into spinal motor neurons via the peripheral nervous system may exacerbate neuronal degeneration in ALS.
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PMID:Aluminum-induced model of motor neuron degeneration: subperineurial injection of aluminum in rabbits. 858 74

Dominant mutations of the SOD1 gene encoding Cu,Zn superoxide dismutase have been found in members of certain families with familial amyotrophic lateral sclerosis (ALS). To better understand the contribution of SOD1 mutations in the pathogenesis of familial ALS, we developed transgenic mice expressing one of the mutations found in familial ALS. These animals display clinical and pathological features closely resembling human ALS. Early changes observed in these animals were intra-axonal and dendritic vacuoles due to dilatation of the endoplasmic reticulum and vacuolar degeneration of mitochondria. We have reported that the Golgi apparatus of spinal cord motor neurons in patients with sporadic ALS is fragmented and atrophic. In this study we show that spinal cord motor neurons of transgenic mice for an SOD1 mutation display a lesion of the Golgi apparatus identical to that found in humans with sporadic ALS. In these mice, the stacks of the cisternae of the fragmented Golgi apparatus are shorter than in the normal organelle, and there is a reduction in Golgi-associated vesicles and adjacent cisternae of the rough endoplasmic reticulum. Furthermore, the fragmentation of the Golgi apparatus occurs in an early, presymptomatic stage and usually precedes the development of the vacuolar changes. Transgenic mice overexpressing the wild-type human superoxide dismutase are normal. In familial ALS, an early lesion of the Golgi apparatus of motor neurons may have adverse functional effects, because newly synthesized proteins destined for fast axoplasmic transport pass through the Golgi apparatus.
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PMID:The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease. 864 99

We studied the possible impairment of fast axonal transport in patients with amyotrophic lateral sclerosis (ALS) to gain some insight into the pathogenesis of the disease. We carried out an ultrastructural investigation of the proximal axons (axon hillock and initial segment) of the anterior horn neurons on samples from 11 ALS patients; specimens from 12 age-matched individuals who died of nonneurological diseases served as controls. Eighty-seven proximal axons that emanated directly from normal-appearing neurons were examined in each group of subjects. Increased smooth endoplasmic reticulum (SER) and the formation of bundles of fibrillary SER with a single unit membrane were not uncommonly observed in the initial segment of the patients with ALS. In some instances, there was loss of the parallel SER arrangement along the longitudinal axis. When viewed in transverse sections, the bundles had a tubular appearance. These morphologic changes of SER were exclusively demonstrated in patients with ALS. A marked increase or accumulation of mitochondria and lysosomes was more common in the proximal axons, particularly in the axon hillock, of ALS patients than of control subjects. The accumulation of these membrane-bounded cytoplasmic organelles suggests that fast axonal transport is impaired in the proximal axons of individuals with ALS. In addition, there were Lewy body-like hyaline inclusions, lipofuscin granules, and multiple membranous structures in the proximal axons. The presence of these unusual structures may also be a reflection of axonal transport dysfunction. By contrast, in the central chromatolytic neurons, there was not only a decrease in the number of neurofilaments in the axon hillock and initial segment, but also of mitochondria, lysosomes, and SER. In some instances, none of these cytoplasmic organelles was seen. These findings support the notion that the outflow of cytoplasmic constituents from the anterior horn cell body into the proximal axon may be impaired in central chromatolytic neurons.
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PMID:Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis. 875 33

A superoxide dismutase 1 (SOD-1)genetic defect has been identified in familial amyotrophic lateral sclerosis (ALS) and motor neuron degeneration has been described in SOD-1 transgenic mice. Because an excitotoxic mechanism has been implicated in ALS, we undertook studies to provide a description of excitotoxic degeneration of spinal motor neurons for comparison with the degenerative process observed in SOD-1 transgenic mice. Excitotoxin agonists selective for each of the three major types of inotropic glutamate receptors were applied directly onto the lumbar spinal cord of 21-day old rats following posterior laminectomy. N-methyl-D-aspartate (NMDA) preferentially affected dorsal horn neurons, whereas the non-NMDA agonist, kainic acid, preferentially affected motor neurons. Cytopathological changes in motor neurons closely resembled those described in SOD-1 mice. These changes consist of massively swollen dendritic processes in the presence of well-preserved presynaptic axon terminals; cell bodies of motor neurons filled with vacuoles that originate both from endoplasmic reticulum and mitochondria; pleomorphic changes in mitochondria; axons of motor neuron becoming swollen proximally with accumulation of vacuoles, organelles, filaments, and degeneration products in the swollen segment. The observed changes in motor axons resemble changes described in the spinal cord of ALS patients. These findings are consistent with the proposal that motor neuron degeneration in ALS may be mediated by an excitotoxic process involving hyperactivation with non-NMDA glutamate receptors.
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PMID:Motor neuron degeneration induced by excitotoxin agonists has features in common with those seen in the SOD-1 transgenic mouse model of amyotrophic lateral sclerosis. 878 80

We report a case of a rapidly progressive, fatal non-inflammatory demyelinating disease, distinct from multiple sclerosis and lysosomal disorders, in a patient with progressive dementia. Electron microscopy of stereotactic brain biopsy samples revealed the presence in neurons of sinuous, double-walled cylindrical membranous structures within the cisterns of the endoplasmic reticulum. These structures were 75-80 nm in overall diameter, up to 1.5 mm long and had a 40- to 45-nm diameter core. The possibility that they might be viruses of the Filoviridae or Paramyxoviridae families was considered, but the inclusions differed in key morphological aspects from members of both virus families and there were no supporting clinical or pathological data. Neither was it possible to assign the structures to any other known virus family on the basis of their morphology. Such inclusions have been the subject of only three published reports over the past 20 years. Evidence suggests that they may be confined to human central nervous system neurons, but occur in unrelated disorders (Alzheimer's disease, amyotrophic lateral sclerosis, meningoencephalitis, low-pressure hydrocephalus, demyelination). The possibility that they are formed in certain neurons by an abnormal internal budding process, as a response to a variety of pathological insults, is considered most likely, although an infectious origin (such as an unrecognised virus with variable clinical effect) cannot be ruled out.
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PMID:Large, virus-like sinuous tubules in the endoplasmic reticulum of human neurons: report from a case of encephalopathy and brief critical review. 887 Aug 32

Calcium homeostasis and ultrastructure are altered in motor axon terminals (AT) of amyotrophic lateral sclerosis (ALS) patients and in mice injected with ALS IgG and exhibit increased density of synaptic vesicles and increased intracellular calcium. To develop an immune-mediated passive transfer experimental model of both systemic weakness and altered morphology, mice were inoculated intraperitoneally with anti-motoneuronal IgG. Animals initially manifested muscle stiffness and evidence of autonomic cholinergic hyperactivity. Electron microscopic cytochemistry within 12 hours (h) demonstrated significantly increased density of synaptic vesicles and calcium both in axon terminals of neuromuscular junctions and synaptic boutons on spinal motoneurons. After 24 h the mice were severely weak and premorbid. The number of synaptic vesicles was still larger than normal, but calcium was depleted from axon terminals and synaptic boutons. The motoneuron perikarya demonstrated the dilatation of the Golgi system and the rough endoplasmic reticulum with an increased amount of calcium. The NMDA receptor antagonist, MK-801, and the L-type calcium channel antagonist, Diltiazem, prevented clinical symptoms and some morphological alterations. These data demonstrate that high titer anti-motoneuronal IgG can induce severe weakness and produce similar ultrastructural features of motor axon terminals in human ALS and in mice injected with ALS IgG, and support a key role for calcium in selective vulnerability of motoneurons.
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PMID:Altered calcium homeostasis and ultrastructure in motoneurons of mice caused by passively transferred anti-motoneuronal IgG. 899 Jan 26


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