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)

Small muscle fibres, defined as those of less than 40 microns diameter in the male and 30 microns in the female were encountered in muscle biopsies of patients with spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), polymyositis (PM) and myopathy/dystrophy. Excessive reactivity with NADH-TR in small fibres did not discriminate between neurogenic and myopathic disorders. Quantification of perifascicular atrophic fibres, the number of nuclei in atrophic fibres, or the presence of isolated or grouped small fibres without histochemical kinship to their surrounding fibres did not aid recognition of the disease process in the groups studied. Small fibres which reacted strongly both with NADH-TR and ATPase at pH 9.4 (Type 3 fibres) constituted 38% of small fibres in the biopsies of SMA; 25% in ALS; but only 1% and 2.7% in PM and myopathy/dystrophy respectively. Thus, the presence of small Type 3 fibres in muscle biopsies may be a useful marker for neurogenic disorders in adults.
 ...
PMID:Origin and significance of small muscle fibres in neuromuscular disease. 294 18

In a group of 16 cases with adult-onset chronic proximal spinal muscular atrophy, we performed a morphometric analysis of 88 intramuscular nerves in biopsied biceps brachii muscles and correlated this analysis with clinical and histochemical parameters. The total number of large and small myelinated fibres in all fascicles was reduced to 71%, 23% and 83% of control values, respectively. The percentage reduction of large myelinated fibres for each case was significantly correlated with duration of illness, biceps muscle power and histochemical atrophy factors. Histograms of large intramuscular nerve fascicles showed unimodal distributions and shifts to the left with single peak increases at 1 micron. The densities of small myelinated fibres in large fascicles correlated with counts of 'enclosed' muscle fibres in ATPase preparations. Compared with amyotrophic lateral sclerosis, a lesser reduction of large myelinated fibres, but a greater increase in small myelinated fibres, was noted in adult-onset chronic proximal spinal muscular atrophy. These findings imply that there is a less marked loss of myelinated nerve fibres with more effective reinnervation in adult-onset chronic proximal spinal muscular atrophy than in amyotrophic lateral sclerosis.
 ...
PMID:Clinical and morphometric analysis of biopsied biceps brachii muscles in adult-onset chronic proximal spinal muscular atrophy. With special reference to intramuscular nerves. 340 87

Acetylcholinesterase (AChE) activity was measured in the presence of the specific inhibitor of pseudocholinesterase, iso-OMPA, in plasma from patients with amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), neuromuscular disease controls, and normal controls. Both AChE and Na-K ATPase activities were measured in erythrocyte ghost membranes from ALS and normal controls. Activities of erythrocyte ghost AChE and Na-K ATPase did not differ between ALS and control patients, suggesting that erythrocyte membranes were normal in ALS. However, the activity of plasma AChE in patients with ALS and PMA was increased significantly over plasma activity in disease controls and normal controls. In addition, in an animal model of human PMA, the Wobbler mouse, plasma AChE activity was increased significantly over littermate controls. The explanation for the increase in plasma acetylcholinesterase was not clear; however, a number of potentially useful clinical points followed from this study. First, there was no relationship between a specific subtype of motor neuron disease and the level of AChE activity. Second, AChE activity appeared to vary directly with the duration of PMA but not with the severity of PMA. This did not correlate with either the duration or severity of ALS. Last, plasma AChE activity was normal in about 30% of patients who had motor neuron disease; therefore, AChE assay had limited use in the diagnosis of ALS or PMA.
 ...
PMID:Acetylcholinesterase and ATPases in motor neuron degenerative diseases. 613 69

1. Current opinions on the mechanisms for glutamate-mediated neurotoxicity are reviewed. The protective role of astrocytic high-affinity glutamate transport is also discussed. 2. Low-density seeding of primary astrocytes from rat hemispheres was found to result in the development of reactive-like astrocytes. Typical glial signs of amyotrophic lateral sclerosis (ALS) could not be induced in astrocyte cultures by serum from ALS-patients. 3. Glutamate (100 mumol/L) was found to induce an increase in respiratory activity in primary cultures of astrocytes. This stimulation appeared to be related to the co-transport of Na2+ with glutamate and a resulting activation of Na2+/K(+)-ATPase. Both basal respiration and glutamate-stimulated oxygen consumption was inhibited by organic solvents. 4. Preliminary results show that heavy metals cause an increase in the mitochondrial DNA content at concentrations that have no effect on growth rate or morphology in a glial cell line. This increase was accompanied by an inhibition of oxygen consumption and an increased production of lactate at unaltered ATP levels.
 ...
PMID:Use of primary cultures and continuous cell lines to study effects on astrocytic regulatory functions. 767 42

In mammalian cells, mitochondria provide energy from aerobic metabolism. They play an important regulatory role in apoptosis, produce and detoxify free radicals, and serve as a cellular calcium buffer. Neurodegenerative disorders involving mitochondria can be divided into those caused by oxidative phosphorylation (OXPHOS) abnormalities either due to mitochondrial DNA (mtDNA) abnormalities, e.g., chronic external ophthalmoplegia, or due to nuclear mutations of OXPHOS proteins, e.g., complex I and II associated with Leigh syndrome. There are diseases caused by nuclear genes encoding non-OXPHOS mitochondrial proteins, such as frataxin in Friedreich ataxia (which is likely to play an important role in mitochondrial-cytosolic iron cycling), paraplegin (possibly a mitochondrial ATP-dependent zinc metalloprotease of the AAA-ATPases in hereditary spastic paraparesis), and possibly Wilson disease protein (an abnormal copper transporting ATP-dependent P-type ATPase associated with Wilson disease). Huntingon disease is an example of diseases with OXPHOS defects associated with mutations of nuclear genes encoding non-mitochondrial proteins such as huntingtin. There are also disorders with evidence of mitochondrial involvement that cannot as yet be assigned. These include Parkinson disease (where a complex I defect is described and free radicals are generated from dopamine metabolism), amyotrophic lateral sclerosis, and Alzheimer disease, where there is evidence to suggest mitochondrial involvement perhaps secondary to other abnormalities.
 ...
PMID:Mitochondria and degenerative disorders. 1157 22

Na,K-ATPase plays a critical role in energy metabolism and ion fluxes. Its loss was investigated in the G93A mouse model of amyotrophic lateral sclerosis (ALS) in which the mutation of Cu/Zn superoxide dismutase (SOD1) is thought to lead to aberrant oxidative damage. Observed losses in spinal cord Na,K-ATPase activity exceeded all expectations. All three catalytic subunit isoforms (alpha1, alpha2, alpha3) were reduced, and the global alpha subunit loss affected not just neurons, glia, and myelinated axon tracts but even ependymal and pial membranes. Decreases in Na,K-ATPase activity were greater than losses of protein, and there were losses of Na,K-ATPase alpha, but not beta, subunits. Together, these observations are consistent with selective degradation of the alpha subunit after damage. Overexpression of normal SOD1 does not cause ALS-like symptoms, but it has other known pathological effects. In transgenic mice overexpressed normal human SOD1 had a smaller but still considerable effect on Na,K-ATPase. Furthermore, the nitric oxide-mediated regulatory pathway for Na,K-ATPase inhibition was undetectable in spinal cord tissue slices from mice overexpressing either mutant or normal human SOD1. Na,K-ATPase activity did not respond to nitric oxide donors, and the free radical-dependent step of the pathway could not be bypassed by the addition of the downstream protein kinase G activator, 8-Br-cGMP. The data demonstrate that Na,K-ATPase is vulnerable to aberrant SOD1 activity, making it a potential contributing factor in disease pathology. Moreover, the global cellular distribution of Na,K-ATPase loss indicates that SOD1 overexpression is far-reaching in its pathological effects.
 ...
PMID:Global loss of Na,K-ATPase and its nitric oxide-mediated regulation in a transgenic mouse model of amyotrophic lateral sclerosis. 1251

Motor neuron degeneration characterizes the spinal cord of patients with amyotrophic lateral sclerosis and the Wobbler mouse mutant. Considering that progesterone (PROG) provides neuroprotection in experimental ischemia and injury, its potential role in neurodegeneration was studied in the murine model. Two-month-old symptomatic Wobbler mice were left untreated or received sc a 20-mg PROG implant for 15 days. Both light and electron microscopy of Wobbler mice spinal cord showed severely affected motor neurons with profuse cytoplasmic vacuolation of the endoplasmic reticulum and/or Golgi apparatus and ruptured mitochondria with damaged cristae, a profile indicative of a type II cytoplasmic form of cell death. In contrast to untreated mice, neuropathology was less severe in Wobbler mice receiving PROG; including a reduction of vacuolation and of the number of vacuolated cells and better conservation of the mitochondrial ultrastructure. In biochemical studies, we determined the mRNA for the alpha3 subunit of Na,K-ATPase, a neuronal enzyme controlling ion fluxes, neurotransmission, membrane potential, and nutrient uptake. In untreated Wobbler mice, mRNA levels in motor neurons were reduced by half compared to controls, whereas PROG treatment of Wobbler mice restored the expression of alpha3 subunit Na,K-ATPase mRNA. Therefore, PROG was able to rescue motor neurons from degeneration, based on recovery of histopathological abnormalities and of mRNA levels of the sodium pump. However, because the gene mutation in Wobbler mice is still unknown, further studies are needed to unveil the action of PROG and the mechanism of neuronal death in this genetic model of neurodegeneration.
 ...
PMID:Progesterone neuroprotection in the Wobbler mouse, a genetic model of spinal cord motor neuron disease. 1258 54

Dorfin, a RING-IBR type ubiquitin ligase (E3), can ubiquitylate mutant superoxide dismutase 1, the causative gene of familial amyotrophic lateral sclerosis (ALS). Dorfin is located in ubiquitylated inclusions (UBIs) in various neurodegenerative disorders, such as ALS and Parkinson's disease (PD). Here we report that Valosin-containing protein (VCP) directly binds to Dorfin and that VCP ATPase activity profoundly contributes to the E3 activity of Dorfin. High through-put analysis using mass spectrometry identified VCP as a candidate of Dorfin-associated protein. Glycerol gradient centrifugation analysis showed that endogenous Dorfin consisted of a 400-600-kDa complex and was co-immunoprecipitated with endogenous VCP. In vitro experiments showed that Dorfin interacted directly with VCP through its C-terminal region. These two proteins were colocalized in aggresomes in HEK293 cells and UBIs in the affected neurons of ALS and PD. VCP(K524A), a dominant negative form of VCP, reduced the E3 activity of Dorfin against mutant superoxide dismutase 1, whereas it had no effect on the autoubiquitylation of Parkin. Our results indicate that VCPs functionally regulate Dorfin through direct interaction and that their functional interplay may be related to the process of UBI formation in neurodegenerative disorders, such as ALS or PD.
 ...
PMID:Physical and functional interaction between Dorfin and Valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders. 1545 87

Riluzole is a drug used in the treatment of amyotrophic lateral sclerosis; however, its in vitro action is unclear. In this study, the effect of riluzole on intracellular Ca2+ concentration ([Ca2+]i) in Madin-Darby canine kidney (MDCK) cells was investigated using the Ca2+ -sensitive fluorescent dye, fura-2. Riluzole (100-500 microM) caused a rapid and sustained increase of [Ca2+]i in a concentration-dependent manner (EC50 = 150 microM). Some 40 and 50% of this [Ca2+]i increase was prevented by the removal of extracellular Ca2+ and the addition of La3+, respectively, but was unchanged by dihydropyridines, verapamil and diltiazem. In Ca2+ -free medium, thapsigargin - an inhibitor of the endoplasmic reticulum (ER) Caz+ -ATPase--caused a monophasic [Ca2+]i increase, after which the increasing effect of riluzole on [Ca2+]i was attenuated by 70%; in addition, pre-treatment with riluzole abolished thapsigargin-induced [Ca2+]i increases. U73122, an inhibitor of phospholipase C (PLC), abolished ATP (but not riluzole)-induced [Ca2+]i increases. At concentrations of 250 and 500 microM, riluzole killed 40 and 95% cells, respectively. The cytotoxic effect of riluzole (250 microM) was unaltered by pre-chelating cytosolic Ca2+ with BAPTA. Collectively, in MDCK cells, riluzole rapidly increased [Ca2+]i by stimulating extracellular Ca2+ influx via an La3+ -sensitive pathway and intracellular Ca2+ release from the ER via, as yet, unidentified mechanisms. Furthermore, riluzole caused Ca2+ -unrelated cytotoxicity in a concentration-dependent manner.
 ...
PMID:Effect of riluzole on Ca2+ movement and cytotoxicity in Madin-Darby canine kidney cells. 1693 18

The mechanisms of human mutant superoxide dismutase-1 (mSOD1) toxicity to motor neurons (MNs) are unresolved. We show that MNs in G93A-mSOD1 transgenic mice undergo slow degeneration lacking similarity to apoptosis structurally and biochemically. It is characterized by somal and mitochondrial swelling and formation of DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. p53 and p73 are activated in degenerating MNs, but without nuclear import. The MN death is independent of activation of caspases-1, -3, and -8 or apoptosis-inducing factor within MNs, with a blockade of apoptosis possibly mediated by Aven up-regulation. MN swelling is associated with compromised Na,K-ATPase activity and aggregation. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of superoxide, nitric oxide, and peroxynitrite than MNs in control mice. Nitrated and aggregated cytochrome c oxidase subunit-I and alpha-synuclein as well as nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible nitric oxide synthase (iNOS)-like immunoreactivity, and iNOS gene deletion extends significantly the life span of G93A-mSOD1 mice. Prior to MN loss, spinal interneurons degenerate. These results identify novel mechanisms for mitochondriopathy and MN degeneration in amyotrophic lateral sclerosis (ALS) mice involving blockade of apoptosis, accumulation of MN mitochondria with enhanced toxic potential from distal terminals, NOS localization in MN mitochondria and peroxynitrite damage, and early degeneration of alpha-synuclein(+) interneurons. The data support roles for oxidative stress, protein nitration and aggregation, and excitotoxicity as participants in the process of MN degeneration caused by mSOD1.
 ...
PMID:Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death. 1709 94


1 2 3 4 5 6 Next >>