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)

The history of motor unit number estimation (MUNE) is given, together with brief descriptions of the various methods presently available. A small muscle of the hand contains about 100 motor units and greater numbers are found in larger muscles; beyond 60 years the numbers begin to decline. In ALS approximately half the motor units cease to function within 6 months of the involvement of the motoneuron pool, while in adult spinal muscular atrophy further loss may not occur over several years. The reduction in MUNE values in myotonic dystrophy remains an enigma, but even more curious are the losses and subsequent recoveries occasionally observed in hyperthyroidism and chronic renal failure; possibly, nontransmitting ("silent") synapses are involved. MUNE may also be used to study CNS problems such as hemiplegia and congenital brachial palsy. The availability of more powerful computers for EMG should lead to advances in MUNE.
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PMID:Motor unit estimation: anxieties and achievements. 771 21

The clinical relevance of neurological disorders associated with impaired glucose tolerance(IGT) is reviewed. In this review some neurological diseases, such as, myotonic dystrophy, Crow-Fukase syndrome, Wolfram syndrome (DIDMOAD), Friedreich ataxia, spinal muscular atrophy of the Kennedy-Alter-Sung type, amyotrophic lateral sclerosis, Parkinson-dementia, and MELAS are discussed in relation to, glucose intolerance. Although the etiology of these disorders still remains an enigma, MELAS was caused by an A-to-G mutation at nucleotide position 3243 of the mitochondria genome. An association of "diabetic neuropathy" with IGT appears to be negative. Peripheral nerve function did not differ between IGT and control subjects, whereas autonomic nerve function deviated; an abnormal expiration to inspiration ratio of R-R interval was significantly more common in IGT than in control subjects. In conclusion, diabetes, but not IGT, is associated with peripheral nerve dysfunction.
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PMID:[Neurological disorders associated with impaired glucose tolerance]. 891 31

The molecular basis of the selective death of motor neurons in amyotrophic lateral sclerosis (ALS) has been an enigma since its description by Charcot in 1869. In this issue of Neuron, demonstrate a motor neuron-specific death pathway which involves Fas and NO. Remarkably, motor neurons from mice carrying ALS-linked mutant forms of superoxide dismutase 1 (SOD1) exhibit an increased sensitivity to death triggered by Fas but not other insults. These data suggest new insights into the mechanisms of, and potential therapeutic strategies for, death of motor neurons in ALS.
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PMID:Fas(t) balls and Lou Gehrig disease. A clue to selective vulnerability of motor neurons? 1235 97

Several theories on the pathomechanism of amyotrophic lateral sclerosis (ALS) have been proposed: misfolded protein aggregates, mitochondrial dysfunction, increased glutamate toxicity, increased oxidative stress, disturbance of intracellular trafficking, and so on. In parallel, a number of drugs that have been developed to alleviate the putative key pathomechanism of ALS have been under clinical trials. Unfortunately, however, almost all studies have finished unsuccessfully. This fact indicates that the key ALS pathomechanism still remains a tough enigma. Recent studies with autopsied ALS patients and studies using mutant SOD1 (mSOD1) transgenic mice have suggested that endoplasmic reticulum (ER) stress-related toxicity may be a relevant ALS pathomechanism. Levels of ER stress-related proteins were upregulated in motor neurons in the spinal cords of ALS patients. It was also shown that mSOD1, translocated to the ER, caused ER stress in neurons in the spinal cord of mSOD1 transgenic mice. We recently reported that the newly identified ALS-causative gene, vesicle-associated membrane protein-associated protein B (VAPB), plays a pivotal role in unfolded protein response (UPR), a physiological reaction against ER stress. The ALS-linked P56S mutation in VAPB nullifies the function of VAPB, resulting in motoneuronal vulnerability to ER stress. In this review, we summarize recent advances in research on the ALS pathomechanism especially addressing the putative involvement of ER stress and UPR dysfunction.
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PMID:ER stress and unfolded protein response in amyotrophic lateral sclerosis. 1918 63

The identification of TDP-43 as the major component of the pathologic inclusions in most forms of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) resolved a long-standing enigma concerning the nature of the ubiquitinated disease protein under these conditions. Anti-TDP-43 immunohistochemistry and the recent development of novel tools, such as phosphorylation-specific TDP-43 antibodies, have increased our knowledge about the spectrum of pathological changes associated with FTLD-U and ALS and moreover, facilitated the neuropathological routine diagnosis of these conditions. This review summarizes the recent advances in our understanding on the molecular neuropathology and pathobiology of TDP-43 in FTLD and ALS.
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PMID:Molecular neuropathology of TDP-43 proteinopathies. 1933 44

Although tremendous progress has been made in recent years in identifying molecular mechanisms of small interfering RNA (siRNA) functions in higher plants, the possibility of direct interaction between genomic DNA and siRNA remains an enigma. Such an interaction was proposed in the 'RNA cache' hypothesis, in which a mutant allele is restored based on template-directed gene conversion. To test this hypothesis, we generated transgenic Arabidopsis thaliana plants conditionally expressing a hairpin dsRNA construct of a mutated acetolactate synthase (mALS) gene coding sequence, which confers chlorsulfuron resistance, in the presence of dexamethasone (DEX). In the transgenic plants, suppression of the endogenous ALS mRNA expression as well as 21-nt mALS siRNA expression was detected after DEX treatment. After screening >100,000 progeny of the mALS siRNA-induced plants, no chlorsulfuron-resistant progeny were obtained. Further experiments using transgenic calli also showed that DEX-induced expression of mALS siRNA did not affect the number of chlorsulfuron-resistant calli. No trace of cytosine methylation of the genomic ALS region corresponding to the dsRNA region was observed in the DEX-treated calli. These results do not necessarily disprove the 'RNA cache' hypothesis, but indicate that an RNAi machinery for ALS mRNA suppression does not alter the ALS locus, either genetically or epigenetically.
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PMID:An attempt to detect siRNA-mediated genomic DNA modification by artificially induced mismatch siRNA in Arabidopsis. 2427 23

Traumatic brain injury (TBI) has been predicted to be a predisposing factor for amyotrophic lateral sclerosis (ALS) and other neurological disorders. Despite the importance of TBI in ALS progression, the underlying cellular and molecular mechanisms are still an enigma. Here, we examined the contribution of TBI as an extrinsic factor and investigated whether TBI influences the susceptibility of developing neurodegenerative symptoms. To evaluate the effects of TBI in vivo, we applied mild to severe trauma to Drosophila and found that TBI leads to the induction of stress granules (SGs) in the brain. The degree of SGs induction directly correlates with the level of trauma. Furthermore, we observed that the level of mortality is directly proportional to the number of traumatic hits. Interestingly, trauma-induced SGs are ubiquitin, p62 and TDP-43 positive, and persistently remain over time suggesting that SGs might be aggregates and exert toxicity in our fly models. Intriguingly, TBI on animals expressing ALS-linked genes increased mortality and locomotion dysfunction suggesting that mild trauma might aggravate neurodegenerative symptoms associated with ALS. Furthermore, we found elevated levels of high molecular weight ubiquitinated proteins and p62 in animals expressing ALS-causing genes with TBI, suggesting that TBI may lead to the defects in protein degradation pathways. Finally, we observed that genetic and pharmacological induction of autophagy enhanced the clearance of SGs and promoted survival of flies in vivo. Together, our study demonstrates that trauma can induce SG formation in vivo and might enhance neurodegenerative phenotypes in the fly models of ALS.
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PMID:Traumatic injury induces stress granule formation and enhances motor dysfunctions in ALS/FTD models. 2943 63

Amyotrophic lateral sclerosis (ALS) is a devastating, neurodegenerative motor neuron disease. The aetiology of ALS remains an enigma which hinders the design of an effective treatment to prevent, postpone, or reverse the pathophysiological changes occurring during the aggressive progression of this disease. During the last decade, basic research within the innate immune system, and in particular the complement system, has revealed new, important roles of the innate immune system during development, homeostasis, and ageing within as well as outside the central nervous system. Several lines of evidence indicate that aberrant activation of the complement system locally in the central nervous system as well as systemically may be involved in the pathophysiology of ALS. This exciting new knowledge could point towards the innate immune system as a potential target of medical intervention in ALS. Recently, the historic perception of ALS as a central neurodegenerative disease has been challenged due to the significant amount of evidence of a dying-back mechanism causing the selective destruction of the motor neurons, indicating that disease onset occurs outside the borders of the blood-brain-barrier. This review addresses the function of the innate immune system during ALS. We emphasize the role of the complement system and specifically suggest the involvement of ficolin-3 from the lectin pathway in the pathophysiology of ALS.
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PMID:Amyotrophic lateral sclerosis: The complement and inflammatory hypothesis. 2993 90