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)

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

We aimed to perform a prospective long-term follow-up of health-related quality of life (QOL) in ALS and to investigate the relationship of personality factors with changes in QOL and disease progression. Data on QOL were collected prospectively for 12 months from 31 ALS patients. Personality factors were studied using the NEO-FFI (NEO Five Factor Inventory). Monthly self-ratings of global QOL, and seven health-related QOL functions, as well as ALSFRS (ALS Functional Rating Scale) scores were analyzed using a linear mixed model approach. QOL and ALSFRS scores decreased during follow-up. Patients who scored higher on the agreeableness personality dimension, despite similar total duration of disease, had higher QOL at the beginning of the follow-up period but the reduction of QOL over time was significantly steeper than in patients who scored lower on agreeableness, associated with faster disease progression. These findings suggest that being less agreeable might serve as a protective factor with respect to QOL and disease progression in ALS.
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PMID:The influence of personality factors on disease progression and health-related quality of life in people with ALS. 1842 2

The Tar DNA-Binding Protein 43 (TDP-43) and its phosphorylated isoform (pTDP-43) are the major components associated with ubiquitin positive/Tau-negative inclusions found in neurons and glial cells of patients suffering of amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration-TDP-43 (FTLD-TDP). Many studies have revealed that TDP-43 is also in the protein inclusions associated with neurodegenerative conditions other than ALS and FTLD-TDP, thus suggesting that this protein may be involved in the pathogenesis of a variety of neurological disorders. In brains of Huntington-affected patients, pTDP-43 aggregates were shown to co-localize with mutant Huntingtin (mHtt) inclusions. Here, we show that expression of mHtt carrying 80-97 polyglutamines repeats in human cell cultures induces the aggregation and the phosphorylation of endogenous TDP-43, whereas non-pathological Htt with 25 polyglutamines repeats has no effect. Mutant Htt aggregation precedes accumulation of pTDP-43 and pTDP-43 co-localizes with mHtt inclusions reminding what it was previously described in brains of Huntington-affected patients. Detergent-insoluble fractions from cells expressing mHtt and containing mHtt-pTDP-43 co-aggregates can function as seeds for further TDP-43 aggregation in human cell culture. The human cellular prion protein PrPC was previously identified as a negative modulator of mHtt aggregation; here, we show that PrPC-mediated reduction of mHtt aggregation is tightly correlated with a decrease of TDP-43 aggregation and phosphorylation, thus confirming the close relationships between TDP-43 and mHtt.
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PMID:Phosphorylated and aggregated TDP-43 with seeding properties are induced upon mutant Huntingtin (mHtt) polyglutamine expression in human cellular models. 3086 8