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)

The histological identification of ubiquitin-conjugated protein deposits in spinal motor neurones of patients with amyotrophic lateral sclerosis (ALS) has suggested that an underlying abnormality of intracellular protein metabolism may be responsible for the pathogenesis of the disease. In an attempt to identify such an abnormality at the biochemical level, we have undertaken a systematic investigation of a representative range of proteolytic enzyme types comprising the two major pathways (cytoplasmic and lysosomal) of intracellular protein degradation, in spinal cord tissue from ALS and control cases. No evidence of a generalised alteration in protein catabolizing proteolytic enzymes in spinal cord tissue from ALS cases was found. Only proline endopeptidase and pyroglutamyl aminopeptidase (both cytoplasmic proteases) showed significantly altered activity (increased by 76% and 119%, respectively) in ALS cases compared to normal controls. In addition to their generalised role in intracellular protein degradation, these two enzymes are involved in the processing of thyrotrophin-releasing hormone (TRH) in CNS tissues. The selective increase in activity of proline endopeptidase and pyroglutamyl aminopeptidase in ALS may represent an adaptation to maintain excitatory drive to surviving motor neurons by increased processing of TRH to its active metabolite.
 ...
PMID:Cytoplasmic, lysosomal and matrix protease activities in spinal cord tissue from amyotrophic lateral sclerosis (ALS) and control patients. 889 62

This report concerns a case of sporadic amyotrophic lateral sclerosis (ALS) with dementia and Lewy body-like hyaline inclusions (LBHIs). The patient was a 70-year-old woman who initially showed memory disturbance and later developed bulbar palsy, muscle atrophy and weakness. The total clinical course was 51 months. The postmortem examination revealed superficial sponginess and subcortical gliosis in the frontotemporal cortices. Ubiquitin-positive intraneuronal inclusions were found in small cortical neurons of the frontotemporal lobe. Neuronal loss was marked in the spinal anterior horn with degeneration of the pyramidal tracts. The anterior horn cells had ubiquitin-immunoreactive skein-like inclusions and Bunina bodies. LBHIs were present in the lumbar horn; ultrastructurally they were composed of randomly arranged thick filamentous structures studded with granules. The LBHIs were intensely stained with anti-ubiquitin antibody. As in familial ALS and in certain cases of sporadic ALS, some of these inclusions reacted with an antibody against Cu/Zn superoxide dismutase, the enzyme whose gene was recently found to be mutated in some forms of familial ALS.
 ...
PMID:Sporadic amyotrophic lateral sclerosis with dementia and Cu/Zn superoxide dismutase-positive Lewy body-like inclusions. 899 56

We analyze neuronal cytopathology and secondary reactions in spinal-muscular atrophy (SMA) in comparison with amyotrophic lateral sclerosis (ALS). In a series of SMA and ALS cases, immunohistochemistry was performed on spinal cord sections for neuronal, astroglial and microglial antigens, ubiquitin and tau proteins. Swollen motoneurons staining for phosphorylated neurofilament proteins are seen in most SMA but few ALS cases. Ubiquitinated inclusions are found only in ALS. In SMA, glial bundles are prominent in anterior roots, to lesser extent in posterior roots. In ALS, glial bundles are seen only in some cases. While basic histopathologies are similar in both types of motor neurone diseases, neuronal cytoskeletal pathology is more prominent in SMA, possibly reflecting a more acute degenerative process. The presence of axon spheroids and glial bundles also in posterior horns/roots of both types of motor neurone disease suggests spread of degenerative pathology beyond the motor system.
 ...
PMID:[Spinal pathology in spinal muscular atrophy in comparison with amyotrophic lateral sclerosis]. 901 11

High levels of familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 mutants G93A and G37R were previously shown to mediate disease in mice through an acquired toxic property. We report here that even low levels of another mutant, G85R, cause motor neuron disease characterized by an extremely rapid clinical progression, without changes in SOD1 activity. Initial indicators of disease are astrocytic inclusions that stain intensely with SOD1 antibodies and ubiquitin and SOD1-containing aggregates in motor neurons, features common with some cases of SOD1 mutant-mediated ALS. Astrocytic inclusions escalate markedly as disease progresses, concomitant with a decrease in the glial glutamate transporter (GLT-1). Thus, the G85R SOD1 mutant mediates direct damage to astrocytes, which may promote the nearly synchronous degeneration of motor neurons.
 ...
PMID:ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. 905 2

We performed post-mortem examinations of three patients with progressive neurogenic amyotrophy of long duration. One patient had been clinically diagnosed as having sporadic amyotrophic lateral sclerosis (ALS) and two had been diagnosed with progressive spinal muscular atrophy (PSMA). The disease durations were 10, 17 and 20 years, respectively, and all of the patients died of respiratory failure with no artificial respiratory support. In all of the patients, both the upper and lower motor neuron systems were affected; degeneration of the former was definite, but was milder than that usually encountered in sporadic ALS patients, and the histopathology of the latter was identical to that of sporadic ALS. Light microscopy revealed Bunina bodies, which are characteristic of sporadic ALS, in the remaining anterior horn cells of each patient. In addition, ubiquitin-positive skein-like inclusions were also identified, immunohistochemically, in the remaining anterior horn cells of each patient. Neuron counts indicated that the number of neurons was preserved in Clarke's column in these patients, but was significantly reduced in the intermediolateral nucleus, compared with control subjects. Based on these findings, we think that these three patients, with long disease durations, were affected by essentially the same underlying disease process as that of sporadic, classical ALS. Moreover, we question the neuropathological occurrence of sporadic ALS without involvement of the upper motor neuron system, namely, pure PSMA or lower motor neuron disease.
 ...
PMID:Neuropathology of sporadic amyotrophic lateral sclerosis of long duration. 907 10

This report concerns an investigation on ubiquitin immunoreactivity in the neuronal perikarya of hippocampal granular cells in Guamanian amyotrophic lateral sclerosis (G-ALS) and Guamanian parkinsonism-dementia complex (G-PDC). Specimens from two non-Guamanian cases of ALS with dementia (ALS-D) were included for comparison. Histologically normal hippocampi from five adults served as controls. Antibodies to ubiquitin and tau protein were used throughout. Most Guamanian patients examined had granular cells with perikaryal ubiquitin immunoreactivity in the dentate gyrus, but in comparison to ALS-D, the frequency of ubiquitin-positive neurons was significantly lower. Tau-positive granular cells were detected in most Guamanian patients, but not in ALS-D. There was a relationship between the numbers of ubiquitin-positive and tau-positive neurons in the dentate granular cell layer of G-ALS and G-PDC patients. This was verified on sections double immunostained for tau protein and ubiquitin. The present findings suggest that the ubiquitin-positive materials observed in the perikarya of the dentate granular cells of patients with G-ALS or with G-PDC seem to be Alzheimer's neurofibrillary tangles rather than the typical ubiquitin-positive intracytoplasmic neuronal inclusions, characteristics of ALS-D. Our data would indicate that different mechanisms are involved in the geneses of cortical neuronal degeneration and decline in cognitive function in ALS-D, G-ALS and G-PDC.
 ...
PMID:Comparative study of ubiquitin immunoreactivity of hippocampal granular cells in amyotrophic lateral sclerosis with dementia, Guamanian amyotrophic lateral sclerosis and Guamanian parkinsonism-dementia complex. 908 58

The Onufrowicz (Onuf's) nuclei from eight amyotrophic lateral sclerosis (ALS) cases and nine neurological control cases were studied histologically and morphometrically. To clarify the factors relating to the involvement of the Onuf's nucleus in ALS, we correlated the relationships among the age at death, clinical duration, morphometric findings for Onuf's neurons, and neuronal numbers in the posteroposterolateral (PPL) nuclei in the ALS cases with those in neurological controls. Intracytoplasmic inclusions such as Bunina bodies, ubiquitin-reactive inclusions, and conglomerate inclusion were found in the Onuf's neurons in ALS, but not in the controls. The total number of Onuf's neurons in the ALS cases was not decreased, but that of normal-appearing neurons was decreased while that of atrophic neurons was increased. Significantly decreased perikaryal, nuclear and nucleolar areas and decreased perikaryal (P)/nuclear and P/nucleolar area ratios of Onuf's neurons were found in ALS, not only in the atrophic neurons but also in the normal-appearing neurons, compared with the controls. The shrinkage in Onuf's neurons of ALS was different from that seen in the ageing process or in the axonal reactions of controls with atonic bladder. In ALS, the morphometric findings for the Onuf's neurons showed no correlation with age at death, clinical duration, or number of PPL neurons. Our results indicate that in ALS Onuf's nucleus is principally vulnerable to the ALS process, although the degree of degeneration differs from that seen in other motor neurons. The involvement of Onuf's nucleus might be slowed due to factors specific to this nucleus, including the biochemical and autonomic properties of the nucleus; nevertheless, it is histologically classified as part of the somatic cell column.
 ...
PMID:Involvement of Onuf's nucleus in amyotrophic lateral sclerosis. 909 64

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons in the spinal cord and brain stem. About 10% of all ALS cases are familial (FALS), inherited in an autosomal dominant manner. One fifth of FALS patients carry mutations in the Cu/Zn superoxide dismutase (SOD1) gene, and several lines of transgenic mice have been engineered to express mutant forms of the SOD1 gene that are linked to FALS. Significantly, many of these transgenic lines of mice develop a motor neuron disease (MND) that resembles human FALS. Oxidative stress induced by human SOD1 mutations is believed to play an important role in the pathogenesis of FALS and the FALS-like MND seen in the mutant SOD1 transgenic mice. For example, two lines of these mice showed prominent degeneration of mitochondria and endoplasmic reticulum in spinal cord neurons. Furthermore, recent studies have shown that neurofilament (NF)-rich spheroids. Lewy body-like NF inclusions, altered ubiquitin immunoreactivity, and Golgi fragmentation occur in the spinal cord motoneurons of these mutant SOD1 transgenic mice. Because these lesions recapitulate hallmark abnormalities of human ALS, mutant SOD1 transgenic mice provide a useful model for studies designed to elucidate the pathogenesis of ALS. Furthermore, transgenic mice that overexpress NF proteins also develop a clinical and pathologic phenotype similar to human MND, and polymorphisms in an NF gene have been linked to patients with ALS. Collectively, these observations implicate NF protein abnormalities in the pathogenesis of this disorder. Accordingly, this review summarizes recent insights into mechanisms of motor neuron degeneration in ALS that have emerged from studies of these new animal models of this neurodegenerative disease.
 ...
PMID:Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease. 911 7

We report the presence of round eosinophilic intranuclear inclusions in a patient with sporadic amyotrophic lateral sclerosis (ALS). The inclusions were limited to the hippocampal pyramidal neurons; they were frequently encountered in the CA1 and CA2 regions and much less frequently in the CA3 and CA4 regions and in the subiculum. Ultrastructurally, they consisted of randomly oriented straight filaments, each about 8-14 nm in diameter, some of which had a tubular appearance in cross-section. Electron-dense, granular material was intermingled with the filaments. Immunohistochemically, all the inclusions were positive for ubiquitin, but were negative for several kinds of cytoskeletal protein, including actin, glial fibrillary acidic protein, vimentin, neurofilament polypeptides, keratin, tubulin, tau protein and microtubule-associated protein 2. To our knowledge, this type of neuronal intranuclear inclusion has not so far been reported in ALS, and its distribution limited to the hippocampal formation is of great interest.
 ...
PMID:Eosinophilic intranuclear inclusions in the hippocampal pyramidal neurons of a patient with amyotrophic lateral sclerosis. 993 Sep 2

Ubiquitin-immunoreactive neuronal inclusions in the granular cells in the dentate fascia (UNIDs) of patients with multiple system atrophy (MSA) were examined for immunohistochemical and ultrastructural characterization especially in comparison with those which were recently reported for amyotrophic lateral sclerosis with dementia (ALS-D). Eight of 23 MSA patients had UNIDs which were also identified by Gallyas-Braak impregnation but immunonegative for other antibodies including against tau, neurofilaments, and alphaB crystallin. Ultrastructurally, loosely aggregated fibrils without limiting membrane located around the nucleus, which was confirmed by the results of ubiquitin-immunoelectron microscopy. The formation of UNIDs in MSA and ALS-D was suggested to be caused by different types of degeneration because UNIDs in MSA differ from these in ALS-D in terms of their stainability by Gallyas-Braak impregnation and ultrastructurally. In this study hippocampal involvement in MSA differing from ALS-D was clarified.
 ...
PMID:Neuronal inclusions in the dentate fascia in patients with multiple system atrophy. 918 74


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