Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Complement proteins of the classical pathway can be immunohistochemically identified in cerebral amyloid plaques in Alzheimer's disease. Microglial cells in and around amyloid plaques express class II major histocompatibility (MHC) antigens and complement receptors CR3 and CR4. Negative immunostaining for immunoglobulins and for T-cell subsets in the brain parenchyma demonstrates a lack of evidence for the involvement of specific immune responses (such as an immune complex-mediated complement activation or a cell-mediated immune response) in cerebral amyloid deposits in Alzheimer's disease. Cerebral amyloid plaques in scrapie-affected mice (slow-virus induced encephalopathy) do not contain complement factors C1q and C3c and are not clustered with microglial cells expressing MHC class II molecules or complement receptor CR3. The data presented suggest the induction of a reactive inflammatory process by beta/A4 amyloid in the human brain, but not by scrapie-induced PrP amyloid in mice. Our findings do not support the hypothesis that the immune system is involved in the generation of amyloid plaques in Alzheimer's disease.
Virchows Arch B Cell Pathol Incl Mol Pathol 1991
PMID:Cerebral amyloid plaques in Alzheimer's disease but not in scrapie-affected mice are closely associated with a local inflammatory process. 168 40

We evaluated cerebrospinal fluid (CSF) antibody levels against a lipid-free, denatured form of myelin basic protein (LF-MBP) in 11 patients with AIDS dementia complex (ADC) by using an enzyme-linked immunosorbent assay (ELISA). In 9 out of 11 patients, anti-LF-MBP antibody levels were significantly higher than those observed both in 15 human immunodeficiency virus (HIV)-infected patients without neurological disorders and in 9 anti-HIV-negative subjects affected by other neurological diseases. Furthermore, we followed up anti-MBP levels in 5 out of the 11 ADC patients and detected a strict relationship with the encephalopathy progression. At the same time, with the aim to detect early demyelinating events we investigated CSF antibody levels against a lipid-bound, native-like form of MBP (LB-MBP). Results did not show any significant difference between LF-MBP and LB-MBP in terms of antibody reactivity. The detection of anti-MBP antibodies in CSF may provide the opportunity to assess a diagnostic tool for discovering demyelinating lesions in ADC patients.
Mol Chem Neuropathol 1991 Jun
PMID:Detection of cerebrospinal fluid antibodies against myelin basic protein in patients with AIDS dementia complex. 172 Mar 16

Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome were fused with human cells lacking endogenous mitochondrial DNA (mtDNA) (rho 0 cells). Selected cybrid lines, containing less than 15 or greater than or equal to 95% mutated genomes, were examined for differences in genetic, biochemical, and morphological characteristics. Cybrids containing greater than or equal to 95% mutant mtDNA, but not those containing normal mtDNA, exhibited decreases in the rates of synthesis and in the steady-state levels of the mitochondrial translation products. In addition, NADH dehydrogenase subunit 1 (ND 1) exhibited a slightly altered mobility on polyacrylamide gel electrophoresis. The mutation also correlated with a severe respiratory chain deficiency. A small but consistent increase in the steady-state levels of an RNA transcript corresponding to 16S rRNA + tRNA(Leu(UUR)) + ND 1 genes was detected. However, there was no evidence of major errors in processing of the heavy-strand-encoded transcripts or of altered steady-state levels or ratios of mitochondrial rRNAs or mRNAs. These results provide evidence for a direct relationship between the tRNALeu(UUR) mutation and the pathogenesis of this mitochondrial disease.
Mol Cell Biol 1992 Feb
PMID:Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. 173 28

Enzymatic and molecular analyses were conducted on the muscular tissue of a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Significant decreases in activity of complexes I and IV were found and three nucleotide substitutions in the mitochondrial tRNA genes were detected. Two of the substitutions were detected in unaffected members of the family and in some healthy controls. A C-to-T transition mutation at the nucleotide position 3,256 in the mitochondrial tRNA(Leu)(UUR) gene was detected only in the patient and not in unaffected members of the family or 100 healthy controls. The data strongly suggest that this mutation at nucleotide position 3,256 in the mitochondrial tRNA(Leu)(UUR) gene is associated with MELAS.
Biochem Mol Biol Int 1994 Aug
PMID:A mitochondrial tRNA(Leu)(UUR) mutation at 3,256 associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). 780 30

In the last 4 years much progress has been made in the understanding of mitochondrial disorders. Point-mutations, deletions and depletion of the mitochondrial genome are associated with disorders like Leber's disease, MERRF (Myoclonus Epilepsia with Ragged Red Fibers), MELAS (mitochondrial Myopathy, Encephalopathy, Lactic acidosis and Stroke-like episodes) and several others. Recently, mitochondrial dysfunctions have been also related to neurodegenerative disorders like Parkinson's disease and to aging. Since the brain depends mostly on mitochondrial energy supply, mitochondrial dysfunctions may affect the nervous system more severely than other tissues causing or worsening diseases and playing a role in the biological deterioration of aging. Furthermore, the mitochondrial energy supply is associated with the production of highly reactive oxygen species. Ninety-five percent of the molecular oxygen is metabolized within the mitochondria by the electron-transport chain so that mitochondria are highly exposed to oxidative stress which may damage selected neuronal populations. Oxygen radicals created during respiration induce mitochondrial dysfunction which accelerates the production of more deleterious species of oxygen. The latter step further increases mitochondrial malfunction, thus intensifying and perpetuating the cycle. These two mechanisms combined may lead to cell death in brain and other tissues with high metabolic rate. Therefore, in neurodegenerative disorders such as Parkinson's disease mitochondrial dysfunction and oxidative stress may cause or worsen the clinical features.
Biochem Mol Biol Int 1994 Aug
PMID:Oxidative stress and mitochondrial dysfunction in neurodegeneration. 784 18

Point mutations in the mitochondrial gene tRNA leucine(UUR) have been associated with maternally inherited mitochondrial myopathies including the MELAS syndrome (Mitochondrial Myopathy Encephalopathy Lactic acidosis and Stroke-like episodes). We describe a further mutation in tRNA leucine(UUR) in a patient with mitochondrial encephalomyopathy, pigmentary retinopathy, dementia, hypoparathyroidism and diabetes mellitus. The mutation was heteroplasmic in the proband's blood (30%) and muscle (76%); it was present at high levels in the proband's affected mother (50% in muscle), and at low levels (< 10%) in blood, muscle and fibroblasts of an unaffected sister. The mutation was not found in 121 normal controls or 35 other patients with mitochondrial disorders. The mutation is at a highly conserved position in the tRNA molecule, close to the 3,243 mutation which is associated with more than 80% of MELAS cases. Further more, both mutations lie within a possible transcriptional control region. This finding adds further support to the evidence that mutations in this region and in other mitochondrial tRNA genes may cause disease.
Hum Mol Genet 1993 Dec
PMID:A new point mutation associated with mitochondrial encephalomyopathy. 811 77

Defects of the respiratory chain carrying out oxidative phosphorylation (OXPHOS) are the biochemical hallmark of human mitochondrial disorders. Faulty OXPHOS can be due to mutations in either nuclear or mitochondrial genes, that are involved in the synthesis of individual respiratory subunits or in their post-translational control. The most common mitochondrial disorder of infancy and childhood is Leigh's syndrome, a severe encephalopathy, often associated with a defect of cytochrome c oxidase (COX). In order to demonstrate which genome is primarily involved in COX-deficient (COX(-))-Leigh's syndrome, we generated two lines of transmitochondrial cybrids. The first was obtained by fusing nuclear DNA-less cytoplasts derived from normal fibroblasts, with mitochondrial DNA-less (rho degree) transformant fibroblasts derived from a patient with COX(-))-Leigh's syndrome. The second cybrid line was obtained by fusing rho degree cells derived from 143B.TK- human osteosarcoma cells, with cytoplasts derived from the same patient. The first cybrid line showed a specific and severe COX(-) phenotype, while in the second all the respiratory chain complexes, including COX, were normal. These results indicate that the COX defect in our patient is due to a mutation of a nuclear gene. The use of cybrids obtained from 'customized', patient-derived rho degree cells can have wide applications in the identification of respiratory chain defects originated by nuclear DNA-encoded mutations, and in the study of nuclear DNA-mitochondrial DNA interactions.
Hum Mol Genet 1995 Nov
PMID:Nuclear DNA origin of cytochrome c oxidase deficiency in Leigh's syndrome: genetic evidence based on patient's-derived rho degrees transformants. 858 77

Aluminum, responsible of dialysis encephalopathy, is suspected to be involved in other neurological disorders such as Alzheimer disease. Absorption of aluminum from the digestive tract can be enhanced by the concommittant intake of substances such as citrate. We studied in rats and mice the interactions between fluoride and aluminum for their digestive absorption and showed that fluoride increased the levels of aluminum in plasma as much as citrate whereas aluminum decreased the absorption of fluoride. This result could be the consequence of the high affinity between aluminum and fluoride which form complexes able to increase the absorption of aluminum and to decrease the absorption of fluoride.
Res Commun Mol Pathol Pharmacol 1996 Feb
PMID:Enhancement of aluminum digestive absorption by fluoride in rats. 883 14

4.1 CURRENT STATUS. While an extensive clinical literature of MRS of muscle, brain, heart and liver has been achieved, the MRS technique is not considered essential for routine diagnosis because it is inherently insensitive and metabolic changes tend to be small. However, MRS techniques have proven to be of considerable value for prognosis in some circumstances, notably for predicting outcome following hypoxic-ischaemic injury in the newborn and also in predicting graft viability following organ transplantation. The chemical specificity of MRS has been illustrated, and exploiting the non-invasive nature of the technique, metabolic fingerprinting of pathophysiological processes throughout the natural history of a wide variety of diseases is now being accomplished. Particularly exciting are the applications of 13C MRS for measuring hepatic and muscle glycogen levels, for example in diabetics, and the use of hepatic 31P MRS for assessing liver function in cirrhosis. Other areas of excitement are the applications of 1H MRS in assessing neuronal function in epilepsy and stroke, and for measuring the evolution of lactate in stroke and hypoxic-ischaemic encephalopathy. Emphasis on technique development continues, and applications still tend to be technology-led. The availability of routine clinical MRI systems with spectroscopy capabilities has given MRS studies wider applicability. The recent improvements in spatial resolution have been impressive and the technique is slowly becoming more quantitative. 4.2. FUTURE PERSPECTIVES. Given the flexibility of clinical magnetic resonance techniques, particularly magnetic resonance imaging, it is likely that MRI will be the diagnostic tool of choice in a wider range of diseases, such as multiple sclerosis, stroke, neurodegenerative conditions, sports injuries and in staging malignancies. Since proton magnetic resonance spectroscopy packages have become a routine addition to many MRI systems, it is feasible to select the MRI sequences of most value in highlighting anatomical and pathological abnormalities and to incorporate specifically selected MRS sequences to emphasize biochemical differences. Improvements in technical methodologies are central to further developments. For example, use of internal coils, such as implantable or endoscopic coils, will enable small regions of tissue to be studied in considerable detail, which may otherwise be inaccessible to measurement. Chemical MRS studies have benefited from the use of higher magnetic fields, and the same may be expected for clinical MRS studies. Whole-body magnets up to 4 T have been used in a few centres, and certainly 3 T systems are becoming more widely available with the recent tremendous interest in functional imaging. Certainly, better control of artefacts can be expected; for example, improved definition of spectral changes due to voluntary or involuntary movements. Wider use of proton decoupling methods will improve the specificity of the spectra, by allowing definitive assignments of overlapping resonances, as well as the sensitivity. Comparing PET and MRS studies, it is becoming increasingly obvious that both will be required in parallel to explore parameters of brain metabolism and function. The ability to measure 13C MR signals in the brain has been demonstrated, which allows measurements of glutamate and glucose turnover. MRS measurements have the advantage of not requiring a radioactive isotope, as well as being insensitive to activity-related changes in regional cerebral blood flow. Also the study of cerebral glucose metabolism by MRS is very promising, allowing a resolution and sensitivity comparable to PET. A combination of MRS and PET studies will allow the pathogenesis of neuropsychiatric disorders to be better understood. (ABSTRACT TRUNCATED)
Prog Biophys Mol Biol 1996
PMID:Development and applications of in vivo clinical magnetic resonance spectroscopy. 902 41

The expression of several mitochondrial and nuclear genes involved in ATP production was examined in cells cultured from muscle biopsies of patients harboring mitochondrial pathologies. The transcript patterns in muscle cells from the patients affected by carnitine palmitoyl transferase II or 2-ketoglutarate dehydrogenase deficiencies were almost similar to control patterns. In the opposite, patterns were strikingly abnormal in all the other cell cultures from patients with defects in enzymatic complexes involved in oxidative phosphorylation: mitochondrial complex II and III deficiencies, two MELAS syndromes (myopathy, encephalopathy, lactic acidosis and stroke like episodes), a case of Kearns-Sayre syndrome and a case of chronic progressive external ophthalmoplegia. In cultured muscle cells from patients with mtDNA mutations, the percentage of mutated mtDNA was low as compared with those determined in the corresponding skeletal muscle biopsy. Moreover, the complex II defect resulting of a nuclear mutation was not expressed in the cell cultures. Thus, an undetermined transcriptional event, transmitted from muscle biopsies to cultured muscle cells, should be involved to account for such abnormal transcript patterns.
Mol Cell Biochem 1997 Mar
PMID:Expression of oxidative phosphorylation genes in muscle cell cultures from patients with mitochondrial myopathies. 906 96


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