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 number of neuropathological markers used for the diagnosis of degenerative dementias is rapidly increasing, and this is somewhat confusing: some lesions described a long time ago, such as ballooned cells, proved to be less specific than they were supposed to be; this is also the case for Lewy bodies, that have been recognised in a larger spectrum of disorders than thought a few years ago. On the contrary, for an increasing number of neuropathologists, Pick bodies are now mandatory for the diagnosis of Pick disease, and this contrasts with the prevalent opinions of the late sixties or seventies. There are a number of reasons for the changing significance of neuropathological markers. Three of them can be easily identified: 1) the burst of immunohistochemistry into neuropathology allowed an easier recognition, a better delineation and new pathophysiological approaches to old lesions, and a dramatic increase in the description of new markers, especially in glial cells; 2) in some conditions characterized by the number and distribution of some lesions rather than by their mere presence, such as aging and Alzheimer disease, a better neuroanatomical point of view permitted new insights into the concept of disease versus age-related changes; 3) more accurate clinicopathologic correlations showed clearly the need of grouping or lumping together some entities: for example, obvious relationship aroused between progressive supranuclear palsy and corticobasal degeneration; in contrast, distinguishing different disorders in the frontal lobe dementias grouped together into "Pick disease" was felt necessary. This review summarizes the main criteria for identification, and the presumed meaning of the chief markers indicating the presence of abnormally phosphorylated tau proteins, A beta peptides, and PrP proteins. Abnormally phosphorylated tau proteins can be stored in the neurons, and participate in the constitution of many lesions (neurofibrillary tangles, neuropil threads, abnormal processes of the crown of neuritic senile plaques, Pick bodies, granulo-vacuolar degeneration, argyrophilic grains). When seen in neuroglia, they are the chief constituents of various lesions that affect mainly astrocytes (abnormal tufts of fibres, astrocytic plaques, thorn-shaped astrocytes, spiny astrocytes) and also oligodendrocytes (oligodendroglial threads and coils, glial cytoplasmic inclusions). A beta peptides, in "preamyloid" and amyloid conformations, can be seen in the extracellular space (plaques, of the neuritic or non-neuritic varieties, diffuse, focal and granular deposits) and in the vascular walls (amyloid angiopathies). Some PrP deposits are also of the amyloid variety (kuru type, multicentric or florid plaques), but immunohistochemistry, far more sensitive than conventional studies, revealed a number of other lesions (perivacuolar, neuronal, "synaptic" deposits...). Numerous markers are easily detected by ubiquitin immunohistochemistry. Lewy bodies, Pick bodies, neurofibrillary tangles had already be identified by other methods. In contrast, some ubiquitin-positive inclusions are shown, by this technique only, in amyotrophic lateral sclerosis and other conditions which were thus related to this disease. Finally, this review deals with two classic markers, ballooned cells ("Pick cells") and spongiosis seen in disorders due to non conventional agents or prions (spongiform encephalopathies).
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PMID:[Neuropathologic markers in degenerative dementias]. 983 44

Data are now rapidly accumulating to show that metallochemical reactions might be the common denominator underlying Alzheimer's disease, amyotrophic lateral sclerosis, prion diseases, cataracts, mitochondrial disorders and Parkinson's disease. In these disorders, an abnormal reaction between a protein and a redox-active metal ion (copper or iron) promotes the formation of reactive oxygen species or radicalization. It is especially intriguing how the powerful catalytic redox activity of antioxidant Cu/Zn-superoxide dismutase can convert into a pro-oxidant activity, a theme echoed in the recent proposal that Abeta and PrP, the proteins respectively involved in Alzheimer's disease and prion diseases, possess similar redox activities.
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PMID:Metals and neuroscience. 1074 95

Metal-catalyzed oxidation may result in structural damage to proteins and has been implicated in aging and disease, including neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis. The selective modification of specific amino acid residues with high metal ion affinity leads to subtle structural changes that are not easy to detect but may have dramatic consequences on physical and functional properties of the oxidized protein molecules. PrP contains a histidine-rich octarepeat domain that binds copper. Because copper-binding histidine residues are particularly prone to metal-catalyzed oxidation, we investigated the effect of this reaction on the recombinant prion protein SHaPrP(29-231). Using Cu2+/ascorbate, we oxidized SHaPrP(29-231) in vitro. Oxidation was demonstrated by liquid chromatography/mass spectrometry, which showed the appearance of protein species of higher mass, including increases in multiples of 16, characteristic of oxygen incorporation. Digestion studies using Lys C indicate that the 29-101 region, which includes the histidine-containing octarepeats, is particularly affected by oxidation. Oxidation was time- and copper concentration-dependent and was evident with copper concentrations as low as 1 microM. Concomitant with oxidation, SHaPrP(29-231) suffered aggregation and precipitation, which was nearly complete after 15 min, when the prion protein was incubated at 37 degrees C with a 6-fold molar excess of Cu2+. These findings indicate that PrP, a copper-binding protein, may be particularly susceptible to metal-catalyzed oxidation and that oxidation triggers an extensive structural transition leading to aggregation.
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PMID:Copper-catalyzed oxidation of the recombinant SHa(29-231) prion protein. 1140 62

Amyotrophic lateral sclerosis (ALS) is a motor neuron degenerative disorder caused in a proportion of cases by missense mutations in the gene encoding Cu/Zn superoxide dismutase (Cu/Zn-SOD) which result in unknown, lethal enzymatic activity. Based on a differential screening approach, we show here that the gene encoding the cellular prion protein (PrP(C)) was specifically repressed in a transgenic model of ALS overexpressing the mutant G86R Cu/Zn-SOD. Analysis by Northern blot, semiquantitative RT-PCR, and Western blot revealed that PrP(C) down-regulation, which appeared early in the asymptomatic phase of the pathology, occurred preferentially in those tissues primarily affected by the disease (spinal cord, sciatic nerve, and gastrocnemius muscle). This down-regulation was not accompanied by refolding of the aberrant PrP(Sc) isoform, the agent which causes transmissible spongiform encephalopathies. Furthermore, modification of PrP(C) expression was specifically linked to the presence of the G86R mutant since no changes were observed in transgenic mice overexpressing wild-type Cu/Zn-SOD. PrP(C) has been shown to play a role in the protection against oxidative stress, and we therefore propose that its down-regulation may contribute at least in part to ALS pathogenesis.
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PMID:Loss of prion protein in a transgenic model of amyotrophic lateral sclerosis. 1186 Feb 74

Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.
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PMID:[Proteins and mutations: a new vision (molecular) of neurodegenerative diseases]. 1213 39

Studies on hereditary CJD and FFI have contributed greatly to the understanding of all forms of prion disease. Most importantly, they have provided strong support for the prion hypothesis [2]. The linkage of pathogenic PRNP mutations to human prion disease strengthens the notion that a change in PrP conformation is a key event that triggers the development of the disease. Although hereditary CJD and FFI account for only 10% of all cases of human prion disease, they provide a unique opportunity for studying disease pathogenesis initiated by perturbation in the PrP structure. An understanding of the events that accompany a change in PrP conformation has far-reaching implications for sCJD (the most common form of the disease) and for sporadic fatal insomnia. A wealth of available evidence indicates that a common pathway in disease pathogenesis may be shared by both the sporadic and the hereditary forms of prion disease, except that the initiating events are stochastic in the former, rather than predetermined by the presence of a germ-line mutation. In addition, investigations of hereditary CJD and FFI have provided plausible mechanisms of phenotypic heterogeneity in prion disease, a phenomenon analogous to the "prion strain" diversity in animal prion disease. Although many other neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's chorea are fairly homogeneous in disease phenotype, prion disease includes many clinically and pathologically distinct disease entities. In hereditary prion disease, the disease phenotype is likely to be determined by the combined effect of pathogenic mutations, codon 129 polymorphism, and the type of PrPSc. The pathogenic mutations include point mutations that are located mostly in the central and C-terminal region of PrP, and deletion and insertion mutations that are located in the N-terminal region. It is conceivable that these distinct types of mutations may result in differential changes in conformation or stability of PrP. The codon 129 polymorphism plays a twofold role in modulating the disease outcome. On the mutant allele, it determines the basic features of the disease phenotype--as in the case of FFI and CJD178--that result respectively from the coupling of M or V at codon 129 with the D178N mutation. On the normal allele, it may modulate the severity of the phenotype. A PrPSc subtype is encoded by the PRNP haplotype, and subsequently is generated by a conformational conversion process that transforms the cellular isoform to the pathogenic protein. The site for the formation of a specific PrPSc conformer and its accumulation in different brain regions are likely to contribute to the clinical features and pathologic lesions. The phenotypic homogeneity in other neurologic diseases, including Alzheimer's disease, may be due, in part, to the lack of a powerful genetic modifier such as the codon 129 polymorphism in the PrP gene, and the lack of the ability of affected gene products such as PrP to assume multiple protein conformations. Clearly, the remaining issue in the understanding of pathogenesis of prion disease is a detailed and accurate knowledge of the in vivo processes and conditions for the formation of PrPSc that inevitably lead to the development and expression of the disease. This knowledge will enable the development of a rational and effective strategy for therapeutic intervention.
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PMID:Hereditary Creutzfeldt-Jakob disease and fatal familial insomnia. 1273 24

Recent investigations of scrapie, Creutzfeldt-Jakob disease (CJD), and chronic wasting disease (CWD) clusters in Iceland, Slovakia and Colorado, respectively, have indicated that the soil in these regions is low in copper and higher in manganese, and it has been well-known that patients of ALS or Parkinson's disease were collectively found in the New Guinea and Papua islands, where the subterranean water (drinking water) contains much Al3+ and Mn2+ ions. Above facts suggest that these neurodegenerative diseases are closely related with the function of a metal ion. We have investigated the chemical functions of the metal ions in detail and established the unique mechanism of the oxygen activation by the transition metal ions such as iron and copper, and pointed out the notable difference in the mechanism among iron, aluminum and manganese ions. Based on these results, it has become apparent that the incorporation of Al(III) or Mn(II) in the cells induces the "iron-overload syndrome", which is mainly due to the difference in an oxygen activation mechanism between the iron ion and Al(III) or the Mn(II) ion. This syndrome highly promotes formation of hydrogen peroxide, and hydrogen peroxide thus produced can be a main factor to cause serious damages to DNA and proteins (oxidative stress), yielding a copper(II)- or manganese(II)-peptide complex and its peroxide adduct, which are the serious agents to induce the structural changes from the normal prion protein (PrP(c)) to abnormal disease-causing isoforms, PrP(Sc), or the formation of PrP 27-30 (abnormal cleavage at site 90 of the prion protein). It seems reasonable to consider that the essential origin for the transmissible spongiform encephalopathies (TSEs) should be the incorporation and accumulation of Al(III) and Mn(II) ions in the cells, and the sudden and explosive increase of scrapie and bovine spongiform encephalopathy (BSE) in the last decade may be partially due to "acid rain", because the acid rain makes Al(III) and Mn(II) ions soluble in the subterranean aquifers.
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PMID:Elucidation of endemic neurodegenerative diseases--a commentary. 1457 44

Japan has been taking measures to cope with intractable diseases centering on five principles: "promoting investigation and research", "providing medical care facilities", "reducing co-payment for medical costs", "improving and coordinating community-based health care", "medical care and welfare services", and "promoting welfare measures aimed at improving the quality of life (QOL)". As the object of measures, 118 diseases including serious neurological diseases (e.g. ALS, CJD, PD etc.) have been specified. Thirty years have passed since the specific diseases treatment research program was launched, during which the environment surrounding intractable diseases has changed significantly. In light of this, "Committee on Measures Against Intractable Diseases" was organized in Sept 2001 under the Health Science Council. Based on the interim report of the committee, the government is going to take new measures against the intractable diseases.
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PMID:[Neurological disease in measures against intractable diseases in Japan]. 1515 63

The pathogenic mechanism(s) underlying neurodegenerative diseases associated with protein misfolding is unclear. Several studies have implicated ER stress pathways in neurodegenerative conditions, including prion disease, amyotrophic lateral sclerosis, Alzheimer's disease and many others. The ER stress response and upregulation of ER stress-responsive chaperones is observed in the brains of patients affected with Creutzfeldt-Jacob disease and in mouse models of prion diseases. In particular, the processing of caspase-12, an ER-localized caspase, correlates with neuronal cell death in prion disease. However, the contribution of caspase-12 to neurodegeneration has not been directly addressed in vivo. We confirm that ER stress is induced and that caspase-12 is proteolytically processed in a murine model of infectious prion disease. To address the causality of caspase-12 in mediating infectious prion pathogenesis, we inoculated mice deficient in caspase-12 with prions. The survival, behavior, pathology and accumulation of proteinase K-resistant PrP are indistinguishable between caspase-12 knockout and control mice, suggesting that caspase-12 is not necessary for mediating the neurotoxic effects of prion protein misfolding.
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PMID:Prion pathogenesis is independent of caspase-12. 1916 19

This paper describes an overview of recent insights concerning some socially relevant neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and Creutzfeldt-Jakob's (CJD) diseases, amyotrophic lateral sclerosis (ALS) and epilepsy. For each pathological state, the direct and/or indirect involvement of P-glycoprotein (P-gp) efflux transport is underlined. On this basis, P-gp still represents an innovative target which can offer new tools for the development of more effective and preventive therapeutic strategies for neurodegenerative disorders. For each of them, therefore, a possible use of drugs affecting P-gp transport activity has been suggested.
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PMID:P-gp transporter and its role in neurodegenerative diseases. 1920 6


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