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

Myelinated fibres in femoral nerves removed from amyotrophic lateral sclerosis (ALS) cases at post mortem were compared with age matched controls. A technique for processing whole transverse sections of the nerves for osmication and subsequent morphometric analysis is described. Although areas depleted in myelinated fibres were seen in the nerves from the ALS group, no statistically significant difference was shown due to wide variations in the controls. However, the ALS nerves showed a degree of disruption in the myelin which was not apparent in the controls. The most obvious effect was widespread "wrinkling" of the myelin in both large and small fibres from the ALS nerves. This phenomenon is the initial stage of a process which eventually results in uneven myelin thickness and nodal swellings and finally myelin ovoids and balls. We illustrate the steps in the progression of this degeneration with teased nerve studies and electron microscopy and propose that there are qualitative changes in the myelin of peripheral nerve in ALS. It seems likely that these are secondary effects resulting from axonal degeneration caused by deterioration and loss of anterior horn cells in the spinal cord.
 ...
PMID:Changes in the myelinated axons of femoral nerve in amyotrophic lateral sclerosis. 836 Jun 62

We tested 13/32 patients with non-familial amyotrophic lateral sclerosis (ALS) positive (41%) for human spuma retrovirus (HSRV) seroreactivity. Half the non-ALS HSRV-positive neurologic patients (12/25) reported multiple fasciculations within the last two years. Sera from four HSRV-env negative ALS patients measurably competed with visna antibodies on maedi-visna antigen. The serologies for bovine leukemia virus, Borna disease virus and GM1IgM-antibodies remained negative. Both visna and foamy virus sequences share epitopes with motor nervous system signal polypeptides, suggesting a retroviral interference with motor neurono-axonal function and neuronotrophic signals.
 ...
PMID:Retroviral interference with neuronotrophic signaling in human motor neuron disease? 839 94

Axonal injury induces cell death in selectively vulnerable motor neurons of immature animals. This extensively studied animal model of trauma-induced motor neuron death is being used to develop the theoretical basis for the therapeutic use of neurotrophic factors to "rescue" dying neurons in amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Antecedent trauma has been implicated as a precipitating factor for amyotrophic lateral sclerosis in susceptible individuals. The animal model of trauma-induced motor neuron death provides support for the concept that motor neurons in individuals susceptible to amyotrophic lateral sclerosis may be selectively vulnerable to trauma producing axonal injury. The case histories of six young adult men who developed amyotrophic lateral sclerosis after trauma with axonal injury are presented.
 ...
PMID:Trauma, axonal injury, and amyotrophic lateral sclerosis: a clinical correlate of a neuropharmacologic model. 863 86

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.
 ...
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

The discovery that some cases of familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) has focused much attention on the function of SOD1 as related to motor neuron survival. Here we describe the creation and characterization of mice completely deficient for this enzyme. These animals develop normally and show no overt motor deficits by 6 months in age. Histological examination of the spinal cord reveals no signs of pathology in animals 4 months in age. However Cu/Zn SOD-deficient mice exhibit marked vulnerability to motor neuron loss after axonal injury. These results indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury.
 ...
PMID:Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. 867 2

Amyotrophic lateral sclerosis (ALS) is a late-onset degenerative disease of motor neurons, characterized by abnormal accumulation of neurofilaments (NFs) in perikarya and proximal axons. Two lines of evidence suggest that neurofilament accumulation can play a crucial role in ALS pathogenesis. First, transgenic mouse models overexpressing NF proteins were found to develop motor neuron degeneration and, second, variant alleles of the NF heavy-subunit (NF-H) gene have been found in some human ALS patients. Our axonal transport studies with transgenic mice overexpressing the human NF-H gene, a model of ALS, revealed defects of intracellular transport not only for neurofilament proteins but also for other cytoskeletal proteins and organelles such as mitochondria. Therefore, we propose that neurofilament accumulation in mice causes neurodegeneration by disrupting axonal transport, a mechanism that may account for the pathogenesis of ALS.
 ...
PMID:A role for neurofilaments in the pathogenesis of amyotrophic lateral sclerosis. 871 77

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.
 ...
PMID:Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis. 875 33

Sera and cerebrospinal fluid (CSF) from 25 patients with amyotrophic lateral sclerosis (ALS) were tested by immunofluorescence on fetal, juvenile and adult central and peripheral neuronal (CNS/PNS) tissues and on nerve biopsy material from affected patients for the presence of autoantibodies. Results were compared with control sera from normal blood donors (n = 45) and patients with other neurological diseases (OND) (n = 11). Three different types of tissue reactivity (glial, axonal, and small blood vessels) were found. Antibodies binding to glial and axonal structures were found in 32% of ALS patients as compared to 12% in normal and 27% in OND controls. In contrast, staining of endothelial cells was found with 24% of ALS sera and CSF but not with normal and OND control sera and was demonstrated only with fetal and juvenile nervous tissue and with suralis nerve biopsies of two of five ALS patients. However, normal or inflamed adult CNS/PNS tissue was not stained with these sera. We conclude that ALS is most likely a heterogeneous group of diseases and only a subgroup of ALS may have an autoimmune pathogenesis. These findings may, therefore, have implications for the evaluation of any immunosuppressive treatment in ALS.
 ...
PMID:Neuronal targets of serum and cerebrospinal fluid autoantibodies in amyotrophic lateral sclerosis. 877 48

Clinical and experimental evidence support an autoimmune etiopathogenesis for amyotrophic lateral sclerosis (ALS). We have shown that local application of ALS-IgG onto nerve terminals induces dysfunction in transmission at the neuromuscular junction. It has been established that IgG and other circulating serum proteins can be taken up by motor nerve terminals, being immunolocalized in the soma where they accumulate following retrograde axonal transport. In the present study, we investigated the presence of human ALS and control IgG in the soma of mouse motoneurons. IgG was applied onto motor nerve terminals of mice by subcutaneous injections on the left levator auris longus muscle which is innervated by a branch of the facial nerve. After several injections, sections of the brainstem containing the facial nuclei were immunoprocessed to detect human IgG. For all IgG tested, motoneuron labeling was significantly more intense in the facial nucleus ipsilateral to the site of injection. In ALS-IgG-treated animals, ipsilateral labeling was significantly stronger than that found on the ipsilateral side of control IgG-treated animals. Our results are compatible with the concept that motoneurons preferentially take up, transport and/or accumulate ALS-IgG. Uptake of pathogenic antibodies by motoneuron terminals may play a role in the pathogenesis of motoneuron disease.
 ...
PMID:Uptake of immunoglobulin G from amyotrophic lateral sclerosis patients by motor nerve terminals in mice. 878 61

An abnormal axonal membrane conductance might contribute to human diabetic neuropathy. To test this idea, we have compared the threshold changes produced by long-lasting (100-200 ms) de- and hyperpolarizing currents applied to median motor and sensory axons at the wrist in 63 diabetic patients with those from 50 normal controls and 27 amyotrophic lateral sclerosis (ALS) patients. Averages of the threshold electrotonus plots for motor and sensory axons of diabetic patients showed more subexcitability during, and slower recovery following, the application of hyperpolarizing currents. Such alterations have been previously found in isolated rat nerves after inhibition of axonal inward rectification by means of cesium ions. The abnormalities in diabetics were positively correlated with the age of patients and the presence of neuropathy. Threshold electrotonus seen in diabetes differed strongly from the effects of acute ischemia and were unlike changes recorded in ALS. The data indicate that an abnormal inward rectification of peripheral axons is associated with diabetic neuropathy. A better understanding of the neurobiology of this conductance might provide information about the pathophysiology of this disease.
 ...
PMID:Abnormal axonal inward rectification in diabetic neuropathy. 880 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>