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)

Because embryonic neurons are more sensitive to the effects of target derived factors than adult neurons, the developing nervous system provides a sensitive model for investigating the in vivo actions of target-derived growth factors. We have used the developing chick embryo to document that skeletal muscle contains substances that selectively enhance the in vivo survival of motor neurons. We have also shown that a single purified skeletal muscle protein (CDF) is capable of rescuing motor neurons during the period of naturally occurring cell death. The rescue of motor neurons in vivo by CDF is consistent with the hypothesis that distinct neurotrophic factors exist which regulate the timing and extent of the naturally occurring death of specific populations of neurons. The effects of CDF appear to be specific for cholinergic somatic motor neurons, since the survival of other types of spinal cord neurons, which also exhibit cell loss during the treatment period, was not affected by CDF treatment. In contrast, treatment of the embryos with extracts of tissues not innervated by motor neurons, or with NGF or bFGF, does not affect motor neuron survival. Thus the ability to rescue motor neurons during the period of cell death appears to be a distinct property of CDF and provides indirect evidence that this molecule may play a role in the survival and development of motor neurons. The role of neurotrophic factor involvement in the pathophysiology of degenerative diseases such as ALS remains entirely speculative. However, the demonstration that such factors affect the neuronal subtypes at risk in these diseases provides experimental support for this possibility.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Skeletal muscle proteins rescue motor neurons from cell death in vivo. 185 84

ALS and chronic spinal muscular atrophy are characterized by wasting of skeletal muscle, suggesting accelerated catabolism or reduced synthesis of muscle protein. We studied seven patients with ALS and three with chronic spinal muscular atrophy using 24-hour urinary 3-methylhistidine excretion as a measure of the rate of muscle catabolism and 24-hour urinary creatinine excretion as an index of significantly and similarly higher in both groups of patients than in controls (p less than 0.0005), implying a state of accelerated skeletal muscle protein catabolism in these diseases.
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PMID:Skeletal muscle catabolism in amyotrophic lateral sclerosis and chronic spinal muscular atrophy. 720 Feb 11

Selenium is an essential micronutrient required for cellular antioxidant systems, yet at higher doses it induces oxidative stress. Additionally, in vertebrates environmental exposures to toxic levels of selenium can cause paralysis and death. Here we show that selenium-induced oxidative stress leads to decreased cholinergic signaling and degeneration of cholinergic neurons required for movement and egg-laying in Caenorhabditis elegans. Exposure to high levels of selenium leads to proteolysis of a soluble muscle protein through mechanisms suppressible by two pharmacological agents, levamisole and aldicarb which enhance cholinergic signaling in muscle. In addition, animals with reduction-of-function mutations in genes encoding post-synaptic levamisole-sensitive acetylcholine receptor subunits or the vesicular acetylcholine transporter developed impaired forward movement faster during selenium-exposure than normal animals, again confirming that selenium reduces cholinergic signaling. Finally, the antioxidant reduced glutathione, inhibits selenium-induced reductions in egg-laying through a cellular protective mechanism dependent on the C. elegans glutaredoxin, GLRX-21. These studies provide evidence that the environmental toxicant selenium induces neurodegeneration of cholinergic neurons through depletion of glutathione, a mechanism linked to the neuropathology of Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.
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PMID:Selenium induces cholinergic motor neuron degeneration in Caenorhabditis elegans. 2256 Sep 97

Protein misfolding is considered to be a potential contributing factor for motor neuron and muscle loss in diseases like Amyotrophic lateral sclerosis (ALS). Several independent studies have demonstrated using over-expressed mutated Cu/Zn-superoxide dismutase (mSOD1) transgenic mouse models which mimic familial ALS (f-ALS), that both muscle and motor neurons undergo degeneration during disease progression. However, it is unknown whether protein conformation of skeletal muscle and spinal cord is equally or differentially affected by mSOD1-induced toxicity. It is also unclear whether heat shock proteins (Hsp's) differentially modulate skeletal muscle and spinal cord protein structure during ALS disease progression. We report three intriguing observations utilizing the f-ALS mouse model and cell-free in vitro system; (i) muscle proteins are equally sensitive to misfolding as spinal cord proteins despite the presence of low level of soluble and absence of insoluble G93A protein aggregate, unlike in spinal cord, (ii) Hsp's levels are lower in muscle compared to spinal cord at any stage of the disease, and (iii) G93ASOD1 enzyme-induced toxicity selectively affects muscle protein conformation over spinal cord proteins. Together, these findings strongly suggest that differential chaperone levels between skeletal muscle and spinal cord may be a critical determinant for G93A-induced protein misfolding in ALS.
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PMID:Differential effects of mutant SOD1 on protein structure of skeletal muscle and spinal cord of familial amyotrophic lateral sclerosis: role of chaperone network. 2388 56

Although the cause of amyotrophic lateral sclerosis (ALS) remains unknown, biological findings suggest that the excitatory amino acid glutamate contributes to the pathogenesis of ALS. In previous studies of ALS, the therapeutic effect of the branched-chain amino acids (BCAAs) leucine, valine and isoleucine has been evaluated. The present study aimed at investigating the acute effect of BCAAs on plasma glutamate levels in ALS patients. Following two oral doses of BCAAs, significantly increased plasma levels were seen for valine (500%), isoleucine (1,377%) and leucine (927%), however the plasma level of glutamate was not affected. The plasma level of several other amino acids (tryptophan, tyrosine, phenylalanine and methionine) were found decreased after oral BCAAs, which may indicate a diminution in the rate of degradation of muscle protein and/or an increase in tissue disposal of amino acids.
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PMID:Effects of branched-chain amino acids on plasma amino acids in amyotrophic lateral sclerosis. 2417 36

Vitamin D has been demonstrated to influence multiple aspects of amyotrophic lateral sclerosis (ALS) pathology. Both human and rodent central nervous systems express the vitamin D receptor (VDR) and/or its enzymatic machinery needed to fully activate the hormone. Clinical research suggests that vitamin D treatment can improve compromised human muscular ability and increase muscle size, supported by loss of motor function and muscle mass in animals following VDR knockout, as well as increased muscle protein synthesis and ATP production following vitamin D supplementation. Vitamin D has also been shown to reduce the expression of biomarkers associated with oxidative stress and inflammation in patients with multiple sclerosis, rheumatoid arthritis, congestive heart failure, Parkinson's disease and Alzheimer's disease; diseases that share common pathophysiologies with ALS. Furthermore, vitamin D treatment greatly attenuates hypoxic brain damage in vivo and reduces neuronal lethality of glutamate insult in vitro; a hallmark trait of ALS glutamate excitotoxicity. We have recently shown that high-dose vitamin D3 supplementation improved, whereas vitamin D3 restriction worsened, functional capacity in the G93A mouse model of ALS. In sum, evidence demonstrates that vitamin D, unlike the antiglutamatergic agent Riluzole, affects multiple aspects of ALS pathophysiology and could provide a greater cumulative effect.
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PMID:Vitamin D as a potential therapy in amyotrophic lateral sclerosis. 2442 61

Muscle denervation at the neuromuscular junction (NMJ), the essential synapse between motor neuron and skeletal muscle, is associated with age-related motor impairment. Therefore, improving muscle innervation at aged NMJs may be an effective therapeutic strategy for treating the impairment. We previously demonstrated that the muscle protein Dok-7 plays an essential role in NMJ formation, and, indeed, its forced expression in muscle enlarges NMJs. Moreover, therapeutic administration of an adeno-associated virus vector encoding human Dok-7 (DOK7 gene therapy) suppressed muscle denervation and enhanced motor activity in a mouse model of amyotrophic lateral sclerosis (ALS). Here, we show that DOK7 gene therapy significantly enhances motor function and muscle strength together with NMJ innervation in aged mice. Furthermore, the treated mice showed greatly increased compound muscle action potential (CMAP) amplitudes compared with the controls, suggesting enhanced neuromuscular transmission. Thus, therapies aimed at enhancing NMJ innervation have potential for treating age-related motor impairment.
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PMID:DOK7 Gene Therapy Enhances Neuromuscular Junction Innervation and Motor Function in Aged Mice. 3275 27