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)

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

This study presents evidence for retrograde axonal transport of exogenous albumin and transferrin in adult brainstem motor neurons, whereas plasma proteins are not transported in neonatal motor neurons. The plasma protein uptake in motor neurons was dose-dependent, suggesting a nonspecific (fluid-phase) uptake mechanism. Further evidence for nonspecific uptake of exogenous transferrin in the motor neuron was found in the presence of transferrin receptor only on the soma and not on the axon terminal. The immunoreaction product of the exogenous plasma proteins was localized as perinuclear granules in association with the lysosomal system, as verified by staining for the lysosomal marker cathepsin D and by ultrastructural examinations. The results suggest that albumin and transferrin derived from hepatic synthesis gain access to motor neurons nonspecifically by retrograde axonal transport, whereas transferrin derived from intracerebral synthesis specifically gains access to motor neurons due to receptor-mediated uptake at the soma of the neuron. The lack of plasma proteins in developing motor neurons suggests that retrograde axonal transport of plasma proteins has no significance for developing axons. Plasma proteins have a potential for transporting toxic metals to motor neurons. Intraneuronal uptake of aluminum-transferrin either by nonspecific uptake in axon terminals or by receptor-mediated uptake at the soma may have a role in the pathogenesis of the motor neuron disease amyotrophic lateral sclerosis.
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PMID:Age-dependent uptake and retrograde axonal transport of exogenous albumin and transferrin in rat motor neurons. 774 35

Acute or chronic aluminum neurotoxicity experiments in the rabbit suggest that aluminum can induce phosphorylation of neurofilamentous proteins. This may result in abnormal resistance to degradation or transport of neurofilament protein and so to the accumulation of neurofilaments in abnormal cells. The possible importance of this process in ALS is considered in relation to the neurofilamentous abnormalities characteristic of intraneuronal inclusions in ALS and in other neurodegenerative disorders.
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PMID:Aluminum neurotoxicity: an experimental approach to the induction of neurofilamentous inclusions. 780 37

Lactotransferrin is a glycoprotein that specifically binds and transports iron. This protein is also believed to transport other metals such as aluminum. Several lines of evidence indicate that iron and aluminum are involved in the pathogenesis of many dementing diseases. In this context, the analysis of the iron-binding protein distribution in the brains of patients affected by neurodegenerative disorders is of particular interest. In the present study, the distribution of lactotransferrin was analyzed by immunohistochemistry in the cerebral cortex from patients presenting with Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, sporadic amyotrophic lateral sclerosis, or Pick's disease. The results show that lactotransferrin accumulates in the characteristic lesions of the different pathologic conditions investigated. For instance, in Alzheimer's disease and Guamanian cases, a subpopulation of neurofibrillary tangles was intensely labeled in the hippocampal formation and inferior temporal cortex. Senile plaques and Pick bodies were also consistently labeled. These staining patterns were comparable to those obtained with antibodies to the microtubule-associated protein tau and the amyloid beta A4 protein, although generally fewer neurofibrillary tangles were positive for lactotransferrin than for tau protein. Neuronal cytoplasmic staining with lactotransferrin antibodies, was observed in a subpopulation of pyramidal neurons in normal aging, and was more pronounced in Alzheimer's disease, Guamanian cases, Pick's disease, and particularly in Down syndrome. Lactotransferrin was also strongly associated with Betz cells and other motoneurons in the primary motor cortex of control, Alzheimer's disease, Down syndrome, Guamanian and Pick's disease cases. These same lactotransferrin-immunoreactive motoneurons were severely affected in the cases with amyotrophic lateral sclerosis. It is possible that in these neurodegenerative disorders affected neurons either take up or synthesize lactotransferrin to an abnormally elevated rate. An excessive accumulation of lactotransferrin, as well as transported iron and aluminum, may lead to a cytotoxic effect resulting in the formation of intracellular lesions and neuronal death.
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PMID:The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis. 795 73

Simultaneous measurements of zinc (Zn) and iron (Fe) concentrations were determined using neutron activation analysis in gray and white matter of the frontal and occipital regions obtained from four patients with parkinsonism-dementia (PD), eight with amyotrophic lateral sclerosis (ALS), and four neurologically normal controls from Guam. Zn content in gray matter from the frontal cortex in ALS and PD cases was significantly decreased, compared with that of controls (p < 0.05). No significant differences were found in the Zn content of white matter from the frontal cortex, and/or gray and white matter from the occipital cortex between the groups. The Zn content in gray matter from both frontal and occipital regions was less in ALS and PD patients than in controls. Fe content in gray matter from the frontal cortex of ALS and PD increased significantly compared with that of controls (p < 0.05). Fe content in white matter from the frontal cortex in PD patients was greater than in controls (p < 0.05), with an overall difference: controls < ALS < PD. These data indicate that an increase in Fe in gray and white matter, and a decrease concentration of Zn in gray matter, combined with an excess and deficiency of bioavailable aluminum and calcium, respectively, may be involved in the pathogenic process of these disorders.
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PMID:Concentrations of zinc and iron in the brains of Guamanian patients with amyotrophic lateral sclerosis and parkinsonism-dementia. 816 89

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

We measured aluminum (Al), calcium (Ca), and iron (Fe) levels in neuronal cytoplasm and nucleus, capillaries, and neuropil in samples of ventral cervical spinal cord from 5 patients with sporadic amyotrophic lateral sclerosis (ALS) and 5 age-matched controls using laser microprobe mass spectrometry (LMMS). The concentration of Al was not altered in any area in the ALS samples. In contrast, Fe and Ca were increased 1.5-2-fold in the nucleus and cytoplasm of ALS neurons but not in capillaries and neuropil. These findings do not support the hypothesis that Al is enriched in spinal cord of sporadic ALS as has been reported for Guamanian ALS/Parkinson's dementia. The elevations of Fe in spinal neurons are consistent with reports of increased Fe in bulk samples of ALS spinal cord. The presence of increased Fe within spinal neurons may be significant in the pathogenesis of motor neuron degeneration by catalyzing the generation of reactive oxygen species within specific cells.
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PMID:Aluminum, calcium, and iron in the spinal cord of patients with sporadic amyotrophic lateral sclerosis using laser microprobe mass spectroscopy: a preliminary study. 858 87

In susceptible species, aluminum induces cytoskeletal changes in which neurofilaments accumulate in neuronal cell bodies and proximal axonal enlargements. To determine if microtubule-associated proteins (MAPs) are altered in this model, we examined the spinal cords of aluminum- and saline-treated control rabbits at several time points after treatment. Transient decreases in tau and MAP2 immunoreactivity in neurons in aluminum-intoxicated rabbits were demonstrated with immunocytochemistry. An antibody directed against Alzheimer's disease paired helical filaments labeled neurons in aluminum-treated rabbits but not controls. MAP5 immunoreactivity in the cell body cytoplasm was displaced by aluminum-induced tangles. The transient decreases in MAP2 and tau immunoreactivity did not reflect alterations in protein levels measured using immunoblotting. The transient antigenic changes in tau and MAP2 may reflect conformational changes in these cytoskeletal proteins. Aluminum-induced pathology provides a model for studying perturbations in MAPs and neurofilament proteins that are characteristic of many human neurodegenerative diseases such as Alzheimer's disease, diffuse Lewy body disease, Parkinson's disease, and amyotrophic lateral sclerosis.
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PMID:Aluminum-induced neuropathology: transient changes in microtubule-associated proteins. 894 45

Amyotrophic lateral sclerosis (ALS) is characterized neuropathologically by chromatolysis, Bunina bodies, hyaline inclusions, skein-like inclusions and axonal spheroids. Aluminum, a known neurotoxin, is the cause of dialysis encephalopathy and is considered to be a causative agent in high incidence foci of ALS in the western Pacific. We have developed an experimental model of motor neuron degeneration in New Zealand white rabbits using chronic low-dose intracisternal administration of aluminum and compared the clinical and neuropathological changes to those of human ALS. Aluminum-inoculated rabbits developed progressive hyperreflexia, hypertonia, limb splaying, gait impairment, muscle wasting, hindlimb paralysis and impaired tonic immobility responses without overt encephalopathic features over a 14-month period. Examination of spinal cords from these animals demonstrated the frequent occurrence and progressive development of anterior horn cell lesions that included small, round, argentophilic perikaryal inclusions similar to hyaline inclusions seen in human ALS. Other inclusions were more condensed and eosinophilic, while still others had neurofibrillary tangle-like morphologies. Axonal spheroids and neuritic thickenings were also prominent and were identical to those seen in human ALS. We believe that the similar and progressive development of neuropathological changes observed in the chronic aluminum-intoxication model, compared to human ALS, warrants further study to aid in understanding the cellular and molecular mechanisms of human motor neuron disease.
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PMID:Comparative study of chronic aluminum-induced neurofilamentous aggregates with intracytoplasmic inclusions of amyotrophic lateral sclerosis. 896 Mar 11

Alterations in cytoskeletal proteins such as the perikaryal accumulation of neurofilaments (NFs) occur in a number of human neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and may contribute to their debilitating effects. The administration of aluminum salts to rabbits induces the aberrant accumulation of NFs within the proximal axons and perikarya of vulnerable neurons and is one animal model which has been extensively studied in an attempt to gain insight into the mechanism(s) of NF perturbations in human disease. Previous studies using Northern blotting techniques to examine mRNA levels in the aluminum-induced neuropathy model have led to seemingly contradictory results. We have used in situ hybridization which provides the cellular resolution needed to: 1) determine whether there are generalized decreases in the levels of mRNA expression or decreases in mRNA encoding specific proteins; 2) determine whether alterations in mRNA levels occur specifically in neurons with NF accumulations; and 3) begin to resolve some of the apparent contradictions in the literature. A moderate dose of aluminum lactate administered on two consecutive days produced neurofibrillary tangles in spinal cord neurons seven days after the first dose. Polyadenylated mRNA levels were not altered in spinal cord neurons in aluminum-treated compared to saline-treated control animals or in tangle-bearing compared to non tangle-bearing neurons in aluminum-treated animals. Middle and high NF subunit (NFH) mRNA levels were not significantly different from polyadenylated mRNA levels in spinal cord neurons in aluminum-treated/control animals. NFH mRNA levels were decreased in neurons containing aluminum-induced NF accumulations. These results suggest that NFH gene expression may be down regulated by an inhibitory feedback mechanism induced by perikaryal accumulations of NFs. This inhibitory feedback regulation for NFH may have implications for neurodegenerative diseases in which NFs accumulate in neuronal perikarya.
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PMID:Neuronal gene expression in aluminum-induced neurofibrillary pathology: an in situ hybridization study. 921 90


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