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)

Peroxiredoxin-ll (Prxll) and glutathione peroxidase-l (GPxl) are regulators of the redox system that is one of the most crucial supporting systems in neurons. This system is an antioxidant enzyme defense system and is synchronously linked to other important cell supporting systems. To clarify the common self-survival mechanism of the residual motor neurons affected by amyotrophic lateral sclerosis (ALS), we examined motor neurons from 40 patients with sporadic ALS (SALS) and 5 patients with superoxide dismutase 1 (SOD1)-mutated familial ALS (FALS) from two different families (frame-shift 126 mutation and A4 V) as well as four different strains of the SOD1-mutated ALS models (H46R/G93A rats and G1H/G1L-G93A mice). We investigated the immunohistochemical expression of Prxll/GPxl in motor neurons from the viewpoint of the redox system. In normal subjects, Prxll/GPxl immunoreactivity in the anterior horns of the normal spinal cords of humans, rats and mice was primarily identified in the neurons: cytoplasmic staining was observed in almost all of the motor neurons. Histologically, the number of spinal motor neurons in ALS decreased with disease progression. Immunohistochemically, the number of neurons negative for Prxll/GPxl increased with ALS disease progression. Some residual motor neurons coexpressing Prxll/GPxl were, however, observed throughout the clinical courses in some cases of SALS patients, SOD1-mutated FALS patients, and ALS animal models. In particular, motor neurons overexpressing Prxll/GPxl, i.e., neurons showing redox system up-regulation, were commonly evident during the clinical courses in ALS. For patients with SALS, motor neurons overexpressing Prxll/GPxl were present mainly within approximately 3 years after disease onset, and these overexpressing neurons thereafter decreased in number dramatically as the disease progressed. For SOD1-mutated FALS patients, like in SALS patients, certain residual motor neurons without inclusions also overexpressed Prxll/GPxl in the short-term-surviving FALS patients. In the ALS animal models, as in the human diseases, certain residual motor neurons showed overexpression of Prxll/GPxl during their clinical courses. At the terminal stage of ALS, however, a disruption of this common Prxll/GPxl-overexpression mechanism in neurons was observed. These findings lead us to the conclusion that the residual ALS neurons showing redox system up-regulation would be less susceptible to ALS stress and protect themselves from ALS neuronal death, whereas the breakdown of this redox system at the advanced disease stage accelerates neuronal degeneration and/or the process of neuronal death.
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PMID:Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models. 1598 30

In G93A mice, the most popular model of amyotrophic lateral sclerosis (ALS), neuronal Lewy-body-like hyaline inclusions (LBHIs) and mitochondria-derived vacuoles are observed in addition to motor neuron loss. Although LBHIs are thought to be toxic, the significance of the mitochondria-derived vacuoles has not been fully investigated. In this study, the relationship between the formation of these vacuoles and LBHIs was clarified statistically in the lumbar segment from two phyletic lines of G93A mice (G1L, G1H), using immunohistochemical methods. Furthermore, the distributions of vacuoles and LBHIs were examined in the pons including the facial nucleus, where pathological changes occur in ALS patients and G93A mice. Numerous vacuoles 2-3 microm in diameter were detected in the neuropil of the lumbar segment from G1L mice euthanatized approximately 3.5 months prior to the onset of the disease. Most of the vacuoles disappeared, but some became larger as the disease progressed. The number of vacuoles with a diameter exceeding 5 microm began to decrease after disease onset, while that of intra-neuritic LBHIs increased rapidly. There was a strong inverse correlation between the numbers of vacuoles and LBHIs in symptomatic mice (P<0.01; G1L, r=-0.91; G1H, r=-0.93). In the facial nucleus of G1L mice, where the number of motor neurons was significantly reduced, only a few LBHIs were detected along with prominent vacuole formation. In contrast, significantly more LBHIs with little vacuole formation were evident around the facial nucleus in G1L mice. Furthermore, the SOD1 immunoreactivity in vacuoles initially increased and then decreased after disease onset. Taken together, the present findings suggest that the mitochondria-derived vacuoles might prevent the formation of LBHIs by sequestering mutated SOD1 from the cytoplasm.
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PMID:Inverse correlation between the formation of mitochondria-derived vacuoles and Lewy-body-like hyaline inclusions in G93A superoxide-dismutase-transgenic mice. 1664 10

Insulin-like growth factor I (IGF-I) has been successfully tested in the SOD1-G93A mouse model of familial amyotrophic lateral sclerosis (ALS) and proposed for clinical treatment. However, beneficial effects required gene therapy or intrathecal application. Circumventing the dosing issues we recently found that polyethylene glycol (PEG) modified IGF-I (PEG-IGF-I) modulated neuromuscular function after systemic application, and protected against disease progression in a motor neuron disease model. Here we investigated its effects in two SOD1-G93A mouse lines, the G1L with a milder and the G1H with a more severe phenotype. Results showed that in G1L mice, PEG-IGF-I treatment significantly improved muscle force, motor coordination and animal survival. In contrast, treatment of G1H mice with PEG-IGF-I or IGF-I even at high doses did not beneficially affect survival or functional outcomes despite increased signalling in brain and spinal cord by both agents. In conclusion, the data point towards further investigation of the therapeutic potential of PEG-IGF-I in ALS patients with less severe clinical phenotypes.
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PMID:Functional improvement in mouse models of familial amyotrophic lateral sclerosis by PEGylated insulin-like growth factor I treatment depends on disease severity. 2287 Oct 74