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)

Rapport et al. (11) reported that marked aberrations in brain ganglioside profiles were present in 17 of 21 patients with ALS. The aberrations were detected both in motor cortex and in unexpected regions such as frontal, temporal, and parahippocampal gyrus cortex. These results suggest that some underlying pathological process in ALS also occurs in some neurons that are less vulnerable than motor neurons to consequent deterioration. Since gangliosides are major membrane constituents whose carbohydrate residues establish structural configurations on the external face of the cell membrane, it is highly probable that aberrant ganglioside patterns reflect alterations in receptor structure and function. Receptors are inherently cell specific and the specificity would account for differences in response of sensory and motor neurons to the pathological process in ALS. An apparent absence of similar ganglioside aberrations in spinal cord suggests that the primary pathology is in the brain. Such aberrations are not seen in Alzheimer's disease. If receptor functions are altered in ALS, what ligands might be involved? A major consideration is neurotrophic hormones (2). Gangliosides are known to modulate the effect of nerve growth factor in some in vitro systems and very recent evidence implicates protein kinase activation as an important mechanism.
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PMID:Implications of altered brain ganglioside profiles in amyotrophic lateral sclerosis (ALS). 213 Jun 65

Previous studies in our laboratory had demonstrated alterations in the physical state of membrane proteins in erythrocytes in Huntington's disease. In order to assess the specificity of our findings, the results of electron spin resonance studies of protein and lipid components, scanning electron-microscopic studies, enzymatic analyses of membrane-bound sodium plus potassium stimulated, magnesium-dependent adenosine triphosphatase and protein kinase, and cell deformability studies of erythrocyte membranes have been performed in the neurological disorders, Huntington's disease, Friedreich's ataxia, Alzheimer's disease, amyotrophic lateral sclerosis, and myotonic and Duchenne muscular dystrophy. Comparison of the results revealed that alterations in the biophysical and biochemical states of erythrocyte membranes in each disorder are specific to the particular disease state with the exception of those in Friedreich's ataxia and Alzheimer's disease. In the latter instance, the clinical and pathological alterations suggest that these two diseases have different primary defects. Our studies suggest that the molecular basis of each disease is different. In addition, the results suggest that biophysical and biochemical investigations of extraneural tissue in Huntington's disease and other neurological disordes have the potential of clarifying the molecular mechanisms by which these diseases arise.
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PMID:Specificity of biophysical and biochemical alterations in erythrocyte membranes in neurological disorders--Huntington's disease, Friedreich's ataxia, Alzheimer's disease, amyotrophic lateral sclerosis, and myotonic and duchenne muscular dystrophy. 625 Nov 75

This article reviews current knowledge of neurofilament structure, phosphorylation, and function and neurofilament involvement in disease. Neurofilaments are obligate heteropolymers requiring the NF-L subunit together with either the NF-M or the NF-H subunit for polymer formation. Neurofilaments are very dynamic structures; they contain phosphorylation sites for a large number of protein kinases, including protein kinase A (PKA), protein kinase C (PKC), cyclin-dependent kinase 5 (Cdk5), extracellular signal regulated kinase (ERK), glycogen synthase kinase-3 (GSK-3), and stress-activated protein kinase gamma (SAPK gamma). Most of the neurofilament phosphorylation sites, located in tail regions of NF-M and NF-H, consist of the repeat sequence motif, Lys-Ser-Pro (KSP). In addition to the well-established role of neurofilaments in the control of axon caliber, there is growing evidence based on transgenic mouse studies that neurofilaments can affect the dynamics and perhaps the function of other cytoskeletal elements, such as microtubules and actin filaments. Perturbations in phosphorylation or in metabolism of neurofilaments are frequently observed in neurodegenerative diseases. A down-regulation of mRNA encoding neurofilament proteins and the presence of neurofilament deposits are common features of human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease. Although the extent to which neurofilament abnormalities contribute to pathogenesis in these human diseases remains unknown, emerging evidence, based primarily on transgenic mouse studies and on the discovery of deletion mutations in the NF-H gene of some ALS eases, suggests that disorganized neurofilaments can provoke selective degeneration and death of neurons. An interference of axonal transport by disorganized neurofilaments has been proposed as one possible mechanism of neurofilament-induced pathology. Other factors that can potentially lead to the accumulation of neurofilaments will be discussed as well as the emerging evidence for neurofilaments as being possible targets of oxidative damage by mutations in the superoxide dismutase enzyme (SOD1); such mutations are responsible for approximately 20% of familial ALS cases.
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PMID:Neurofilaments in health and disease. 975 17

In neurodegenerative diseases such as ALS and AD there is evidence for abnormal regulation of protein kinases. In these diseases, altered activities and protein levels of several specific kinases suggest that abnormal phosphorylation is present and this aberrant phosphorylation may be involved in the pathogenesis of these diseases. The observation that regulation of the NMDA receptor ion channel is altered in tissue from ALS patients may arise from the abnormal phosphorylation state of the protein kinase regulating NMDA receptor function. Whether the abnormalities of these protein kinases is a primary event leading to altered receptor regulation or vice versa is still poorly understood. The seemingly multiple pathogenic mechanisms of ALS and AD create complexity in assessing a primary cause that may lead to cell death. The mechanisms causing cell death (apoptosis or necrosis) may be overlapping with integrated events among the components interacting and contributing to a final pathway for neuron death. Thus, evidence of impairment in protein kinase signalling in these diseases may be a primary cause, a secondary event, or a compensatory mechanism. To further study this issue, different model systems could be beneficial to obtain a better understanding of these diseases.
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PMID:Abnormalities of protein kinases in neurodegenerative diseases. 994 61

Amyotrophic lateral sclerosis is an age-related neurological disease, characterized by neurofilament (NF) accumulation in primary axons followed by degeneration of motor neurons. To elucidate age-related factors that might lead to pathological NF accumulation, NFs were compared between young and aged rats. Electron microscopic examination of sciatic nerve axons revealed that NFs were more than twice as densely packed in aged rat axons (542 +/- 180 NFs/mm2) as in young adult rat axons (211 +/- 73 NFs/mm2). The NFs isolated from aged rats also appeared to be more aggregated than those from young rats. Phosphorylation at the head or tail domains was studied as a possible candidate affecting NF organization. Western blotting with phosphorylation-dependent antibodies showed higher phosphorylation of NF-H in the tail domains of aged rat spinal cord NFs, but dephosphorylation did not diminish the differences in aggregation between aged and young rat NFs. On the other hand, when NFs were phosphorylated by A-kinase on their head domains, the extent of phosphorylation in NF-M of aged rat NFs was only one-third of young rat NFs. We found that aged rat NFs contained only 60% of the NF-M of young rat NFs in molar ratio compared to NF-L. These results raise a possibility that the decreased amount of NF-M induces the aggregates of isolated NFs and the higher packing density of NF in aged rat axons.
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PMID:Neurofilaments of aged rats: the strengthened interneurofilament interaction and the reduced amount of NF-M. 1050 90

Prostate apoptosis response-4 (Par-4) is a 38-kDa protein initially identified as the product of a gene upregulated in prostate tumor cells undergoing apoptosis. Par-4 contains both a death domain and a leucine zipper domain, and has been shown to interact with several proteins known to modulate apoptosis, including protein kinase Czeta, Bcl-2, and caspase-8. A rapid increase in Par-4 levels occurs in neurons undergoing apoptosis in a variety of paradigms, including trophic factor withdrawal, and exposure to oxidative and metabolic insults. Par-4, which can be induced at the translational level, acts at an early stage of the apoptotic cascade prior to caspase activation and mitochondrial dysfunction. The mechanism whereby Par-4 promotes apoptosis may involve inhibition of the antiapoptotic transcription factor NF-kappaB and suppression of Bcl-2 expression and/or function. Studies of postmortem tissues from patients and animal models of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis (ALS), and HIV encephalitis, have documented increased levels of Par-4 in vulnerable neurons. Manipulations that block Par-4 expression or function prevent neuronal cell death in models of each disorder, suggesting a critical role for Par-4 in the neurodegenerative process. Interestingly, Par-4 levels rapidly increase in synaptic terminals following various insults, and such local increases in Par-4 levels appear to play important roles in synaptic dysfunction and degeneration. A better understanding of the molecular and cellular biology of Par-4 will help clarify mechanisms of neuronal apoptosis, and may lead to the development of novel preventative and therapeutic strategies for neurodegenerative disorders.
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PMID:Par-4: an emerging pivotal player in neuronal apoptosis and neurodegenerative disorders. 1069 Dec 89

Riluzole (RP 54274) is a potent neuroprotective agent with anticonvulsant, sedative, and anti-ischemic properties. It is currently used in the treatment of amyotrophic lateral sclerosis. This article reports that riluzole is an activator of TREK-1 and TRAAK, two important members of a new structural family of mammalian background K(+) channels with four transmembrane domains and two pore regions. Whereas riluzole activation of TRAAK is sustained, activation of TREK-1 is transient and is followed by an inhibition. The inhibitory process is attributable to an increase of the intracellular cAMP concentration by riluzole that produces a protein kinase A-dependent inhibition of TREK-1. Mutants of TREK-1 lacking the Ser residue where the kinase A phosphorylation takes place are activated in a sustained manner by riluzole. TRAAK is permanently activated by riluzole because, unlike TREK-1, it lacks the negative regulation by cAMP.
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PMID:The neuroprotective agent riluzole activates the two P domain K(+) channels TREK-1 and TRAAK. 1077 73

The female sex hormone oestradiol (oestrogen) is a steroidal compound that binds to specific intracellular receptors which act as transcription factors. Oestrogen displays many of its effects by the classical mode of action through receptor binding, transactivation and binding to consensus oestrogen response elements on DNA. Although the primary role of oestrogen as an ovarian steroid was thought to be the regulation of sex differentiation and maturation, since oestrogen receptors are expressed in a variety of other tissues besides sex organs, oestrogen is believed to exert multiple activities in several target sites throughout the body, including the nervous system. In the brain oestrogens have multiple activities. Potential neuroprotective functions of oestrogens are being intensively studied and it is becoming increasingly clear that oestrogens are (1) neuroprotective hormones acting via oestrogen receptor-dependent pathways at the genomic level and (2) neuroprotective steroidal structures acting independently of the activation of specific oestrogen receptors. One striking activity of the molecule oestradiol is its intrinsic antioxidant activity which makes it a potential chemical shield for neurons. Nerve cells frequently encounter oxidative challenges during the normal physiology, but also under pathophysiological conditions. Oxidative stress has been implicated in a variety of neurodegenerative disorders including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. It is important to stress that the antioxidant neuroprotective activity of oestrogens is independent of oestrogen receptor activation, since oestrogen derivatives and aromatic alcohols that do not bind to oestrogen receptors share the same antioxidant neuroprotective activity. Although this effect of oestrogens can clearly be separated from oestrogen receptor binding, oestrogens may interact with intracellular signalling pathways, such as the mitogen activated protein kinase, cyclic AMP pathways, and with the activity of the redox-sensitive transcription factor NF-kappa B.
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PMID:The female sex hormone oestrogen as neuroprotectant: activities at various levels. 1096 11

Cdk5, a serine/threonine kinase in the cyclin-dependent kinase (Cdk) family, is an important regulator of neuronal positioning during brain development. Cdk5 might also play a role in synaptogenesis and neurotransmission. Loss of Cdk5 in mice is perinatal lethal, and overactive Cdk5 induces apoptosis in cultured cells, indicating that strict regulation of kinase activity is crucial. Indeed, activity depends on the stability of activating partners, subcellular localization and the phosphorylation state of the enzyme itself. Deregulated kinase activity has been linked to neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). This review focuses on links between Cdk5 activity and components of cytoskeletal, membrane and adhesion systems that allow us to postulate a role for Cdk5 in directing intracellular traffic in neurons.
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PMID:Cdk5 behind the wheel: a role in trafficking and transport? 1185 7

Our current understanding of nitric oxide (NO), cyclic GMP (cGMP) and protein kinase G (PKG) signaling pathways in the nervous systems has its origins in the early studies conducted on vascular tissues during the late 1970s and early to mid-1980s. The pioneering research into the NO/cGMP/PKG pathway in blood vessels conducted by the laboratories of Drs. Ferid Murad, Louis Ignarro and Robert Furchgott ultimately led to the awarding of the 1998 Nobel Prize in Physiology or Medicine to these three scientists. On the basis of further pioneering studies by Drs. John Garthwaite, Solomon Snyder, Steven Vincent and many other neuroscientists during the late 1980s and throughout the 1990s, it became recognized that NO serves as a neurotransmitter/neuromodulator in the central and peripheral nervous systems and that certain neural cells possess a cGMP signaling pathway similar to that in vascular smooth muscle cells. Although NO (at high concentrations) is toxic and thought to participate in neuronal cell death during stroke and neurodegenerative diseases (e.g. amyotrophic lateral sclerosis, Alzheimer's disease, HIV dementia and Parkinson's disease), recent evidence suggests that NO at low physiological concentrations can act as an antiapoptotic/prosurvival factor in certain neural cells (e.g. PC12 cells, motor neurons and neurons of dorsal root ganglia, hippocampus and sympathetic nerves). The antiapoptotic effects of NO are mediated, in part, by cGMP and a downstream target protein, PKG. Other cGMP-elevating factors (e.g. atrial and brain natriuretic peptides) and direct PKG activator (e.g. 8-bromo-cGMP) also have antiapoptotic effects which have been quantified by the new capillary electrophoresis with laser-induced fluorescence detector technology. Inhibition of soluble guanylyl cyclase and lowering of basal cGMP levels cause apoptosis in unstressed neural cells (NG108-15 and N1E-115 cells). The cGMP/PKG pathway appears to play an essential role in preventing activation of a proapoptotic pathway, thus promoting neural cell survival.
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PMID:Involvement of cyclic GMP and protein kinase G in the regulation of apoptosis and survival in neural cells. 1239 44


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