Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0030567 (Parkinson's disease)
63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In humans, complex I dysfunction has been observed in a high percentage of patients with mitochondrial myopathy. Analysis of mitochondria from these patients suggests the function and assembly of complex I is particularly susceptible to abnormalities of mitochondrial DNA, involving either point mutations of tRNA genes or major deletions. The evidence for a complex I defect in Parkinson's disease is accumulating, although the cause of this deficiency or the role it plays in the events that culminate in dopaminergic cell death remains unresolved.
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PMID:Human mitochondrial complex I dysfunction. 163 85

The total sequence data for mitochondrial DNA (mtDNA) revealed distinct clustering of point mutations (pms) in mtDNA among one patient with myoclonus epilepsy with ragged-red fibers (MERRF), two patients with Parkinson's disease (PD), two patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and one patient with fatal infantile cardiomyopathy (FICM). Among 33 to 62 pms found in each patients, sequentially diverged five clusters of pms were detected and designated as C-1 to C-5. C-1, consisted of fourteen pms, existed in the MERRF patient, C-1 and C-2 (nine pms) in one PD patient, C-1 to C-3 (seven pms) in another PD patient, C-1 to C-4 (one pm) in one MELAS patient and C-1 to C-5 (three pms) in another MELAS patient and the FICM patient. From these clustering of pms, a phylogenetic tree of mitochondrial encephalomyopathies (ME) was constructed. This tree clearly indicated that the ME and PD patients are members of the same gene family, and the MELAS and FICM patients are each others' closest relative. Each patient's unique pms (14 to 28 pms) were detected and, from their characteristic features, the types of the mutations specific for the disease were classified as mit- + syn- for MERRF, mit- + p- for PD, and syn- + mit- for MELAS. An inverse relation was found between the total number of pms and life span of the MELAS and FICM patients.
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PMID:Distinct clustering of point mutations in mitochondrial DNA among patients with mitochondrial encephalomyopathies and with Parkinson's disease. 202 3

The activity of complex I of the respiratory chain is decreased in the substantia nigra of patients with Parkinson's disease (PD) but the presence of this defect in skeletal muscle is controversial. Therefore, the mitochondrial function of skeletal muscle in patients with PD was investigated in vivo using 31P magnetic resonance spectroscopy. Results from 7 PD patients, 11 age matched controls and 9 mitochondrial myopathy patients with proven complex I deficiency were obtained from finger flexor muscle at rest, during exercise and in recovery from exercise. In resting muscle, the patients with mitochondrial myopathy showed a low PCr/ATP ratio, a low phosphorylation potential, a high P(i)/PCr ratio and a high calculated free [ADP]. During exercise, stores of high energy phosphate were depleted more rapidly than normal, while in recovery, the concentration of phosphocreatine and free ADP returned to pre-exercise values more slowly than normal. In contrast, the patients with PD were not significantly different from normal for any of these variables, and no abnormality of muscle energetics was detected. Three of the PD patients also had mitochondrial function assessed biochemically in muscle biopsies. No respiratory chain defect was identified in any of these patients by polarography or enzyme analysis when compared with age-matched controls. These results suggest that skeletal muscle is not a suitable tissue for the investigation and identification of the biochemical basis of the nigral complex I deficiency in PD.
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PMID:A 31P magnetic resonance spectroscopy study of mitochondrial function in skeletal muscle of patients with Parkinson's disease. 796 92

The cause and pathophysiology of dystonia remain unknown. The recent identification of mitochondrial complex I deficiency in platelets from patients with sporadic focal dystonia suggests that a defect of energy metabolism may be relevant in a proportion of patients. We have addressed the possible contribution of mitochondrial DNA (mtDNA) to the complex I deficiency in dystonia by the use of genome transfer technology. Platelets from patients deficient for complex I were fused with A549 p0 (mtDNA-less) cells to form cybrids comprising the A549 nucleus and dystonia mtDNA. Mixed cybrid cell lines were analyzed for 9 controls and 9 dystonia patients, and clonal cybrid lines were generated for 2 control and 2 dystonia patients. Subsequent biochemical analysis showed that the dystonia complex I defect was complemented in both the mixed and the clonal cybrid lines. These results contrast with similar studies in mitochondrial myopathy and Parkinson's disease patients, in which the mitochondrial defect was maintained in at least a proportion of A549 cybrids, and suggest that the complex I defect in dystonia is not caused by an mtDNA mutation.
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PMID:Mitochondrial DNA in focal dystonia: a cybrid analysis. 970 50

Pronounced forward flexion of the trunk, often termed camptocormia, is a typical symptom of patients with Parkinson's disease. In 4 parkinsonian patients with camptocormia, paraspinal muscles were studied by electromyography (EMG) and axial computerized tomography (CT) or magnetic resonance imaging (MRI) scans and muscle biopsy. EMG of the lumbar and thoracic paravertebral muscles showed abundant fibrillations, positive sharp waves, and bizarre high-frequency discharges. Spinal CT and MRI scans revealed variable degrees of atrophy and fatty replacement of the thoracolumbar paraspinal muscles on both sides. No other signs of neuromuscular disease were found. Biopsy of the paraspinal muscles revealed end-stage myopathy with autophagic vacuoles, chronic inflammatory myopathy, unspecific myopathic changes, or mitochondrial myopathy. In parkinsonian patients with pronounced forward flexion of the trunk, myopathy confined to the erector spinae muscles must be considered.
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PMID:Severe forward flexion of the trunk in Parkinson's disease: focal myopathy of the paraspinal muscles mimicking camptocormia. 1267 47

A possible role of allelic variation of the mitochondrial DNA polymerase gamma (POLG1) gene in Parkinson's disease (PD) has been suggested. First, POLG1 missense mutations have been found in patients with familial parkinsonism and mitochondrial myopathy. Second, increased frequency of rare alleles of the POLG1 CAG-repeat (poly-Q) has been found in Finnish idiopathic apparently sporadic PD patients, but conflicting reports exist. The POLG1 poly-Q exhibits one major allele with 10 repeats (10Q, frequency >/=80%) and several less common alleles such as 11Q (frequency 6-9%), 6Q-9Q and 12Q-14Q (frequencies <4%). It is not known, whether the poly-Q variation modulates POLG1 function. Here we sequenced the poly-Q in 641 North American Caucasian PD patients and 292 controls. Caucasian literature controls were also used. Normal allele was defined either as 10/11Q or as 10Q according to the previous literature. The frequency of the non-10/11Q alleles in cases was not significantly different from the controls. Variant alleles defined as non-10Q were significantly increased in the PD patients compared to the North American controls (17.6% vs. 12.3%, p=0.004) as well as compared to the larger set of 897 controls (17.6% vs. 13.2%, p=0.0007). These results suggest that POLG1 poly-Q alleles other than the conserved 10Q allele may increase susceptibility to PD. This finding may be attributable to a beneficial function of the 10Q repeat protein or linkage disequilibrium between the 10Q allele and another variation within or close to POLG1. Other large case-control studies and analyses on functional differences of POLG1 poly-Q variants are warranted.
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PMID:POLG1 polyglutamine tract variants associated with Parkinson's disease. 2039 36

Radiolabeled diacetylbis(4-methylthiosemicarbazonato)copper(II) [Cu(II)(atsm)] is an effective positron-emission tomography imaging agent for myocardial ischemia, hypoxic tumors, and brain disorders with regionalized oxidative stress, such as mitochondrial myopathy, encephalopathy, and lactic acidosis with stroke-like episodes (MELAS) and Parkinson's disease. An excessively elevated reductive state is common to these conditions and has been proposed as an important mechanism affecting cellular retention of Cu from Cu(II)(atsm). However, data from whole-cell models to demonstrate this mechanism have not yet been provided. The present study used a unique cell culture model, mitochondrial xenocybrids, to provide whole-cell mechanistic data on cellular retention of Cu from Cu(II)(atsm). Genetic incompatibility between nuclear and mitochondrial encoded subunits of the mitochondrial electron transport chain (ETC) in xenocybrid cells compromises normal function of the ETC. As a consequence of this impairment to the ETC we show xenocybrid cells upregulate glycolytic ATP production and accumulate NADH. Compared to control cells the xenocybrid cells retained more Cu after being treated with Cu(II)(atsm). By transfecting the cells with a metal-responsive element reporter construct the increase in Cu retention was shown to involve a Cu(II)(atsm)-induced increase in intracellular bioavailable Cu specifically within the xenocybrid cells. Parallel experiments using cells grown under hypoxic conditions confirmed that a compromised ETC and elevated NADH levels contribute to increased cellular retention of Cu from Cu(II)(atsm). Using these cell culture models our data demonstrate that compromised ETC function, due to the absence of O(2) as the terminal electron acceptor or dysfunction of individual components of the ETC, is an important determinant in driving the intracellular dissociation of Cu(II)(atsm) that increases cellular retention of the Cu.
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PMID:An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copperII. 2217 33

The neuromuscular literature over the past 3 months has been diverse, including useful information on the epidemiology of several disorders. Our understanding of the genetics of amyotrophic lateral sclerosis continues to grow, and in the process, it makes the distinction between familial and sporadic forms of the disorder increasingly murky. Some interesting articles about peripheral neuropathy provide insight into relationships with diabetes and with Parkinson disease and summarize the state of knowledge of the increasingly complex topic of hereditary neuropathies in children. Epidemiology and electrodiagnosis of lateral femoral cutaneous neuropathy is nicely discussed in 2 articles. Several muscle diseases, including Pompe disease, sporadic inclusion body myositis, and the congenital myopathies, receive attention in articles that provide very useful information for the clinician, and there is a treatment-oriented article on dystrophinopathies, which makes for excellent reading. There are also discussions of several uncommon disorders, including a mitochondrial myopathy, periodic paralysis, and congenital myasthenic syndromes, which are helpful in providing information to clinicians who may see such disorders only infrequently.
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PMID:What's in the literature? 2253 13

Genetic evidence from recessively inherited Parkinson's disease has indicated a clear causative role for mitochondrial dysfunction in Parkinson's disease. This role has long been discussed based on findings that toxic inhibition of mitochondrial respiratory complex I caused parkinsonism and that tissues of patients with Parkinson's disease show complex I deficiency. Disorders of mitochondrial DNA maintenance are a common cause of inherited neurodegenerative disorders, and lead to mitochondrial DNA deletions or depletion and respiratory chain defect, including complex I deficiency. However, parkinsonism associates typically with defects of catalytic domain of mitochondrial DNA polymerase gamma. Surprisingly, however, not all mutations affecting DNA polymerase gamma manifest as parkinsonism, but, for example, spacer region mutations lead to spinocerebellar ataxia and/or severe epilepsy. Furthermore, defective Twinkle helicase, a close functional companion of DNA polymerase gamma in mitochondrial DNA replication, results in infantile-onset spinocerebellar ataxia, epilepsy or adult-onset mitochondrial myopathy, but not typically parkinsonism. Here we sought for clues for this specificity in the neurological manifestations of mitochondrial DNA maintenance disorders by studying mesencephalic neuropathology of patients with DNA polymerase gamma or Twinkle defects, with or without parkinsonism. We show here that all patients with mitochondrial DNA maintenance disorders had neuronopathy in substantia nigra, most severe in DNA polymerase gamma-associated parkinsonism. The oculomotor nucleus was also affected, but less severely. In substantia nigra, all patients had a considerable decrease of respiratory chain complex I, but other respiratory chain enzymes were not affected. Complex I deficiency did not correlate with parkinsonism, age, affected gene or inheritance. We conclude that the cell number in substantia nigra correlated well with parkinsonism in DNA polymerase gamma and Twinkle defects. However, complex I defect is a general consequence of mitochondrial DNA maintenance defects, and does not explain manifestation of parkinsonism or degree of mesencephalic cell death in patients with mitochondrial DNA maintenance disorders.
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PMID:Mesencephalic complex I deficiency does not correlate with parkinsonism in mitochondrial DNA maintenance disorders. 2381 24

The coiled-coil-helix-coiled-coil-helix domain (CHCHD)-containing proteins are evolutionarily conserved nucleus-encoded small mitochondrial proteins with important functions. So far, nine members have been identified in this protein family. All CHCHD proteins have at least one functional coiled-coil-helix-coiled-coil-helix (CHCH) domain, which is stabilized by two pairs of disulfide bonds between two helices. CHCHD proteins have various important pathophysiological roles in mitochondria and other key cellular processes. Mutations of CHCHD proteins have been associated with various human neurodegenerative diseases. Mutations of CHCHD10 are associated with amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobe dementia (FTD), motor neuron disease, and late-onset spinal muscular atrophy and autosomal dominant mitochondrial myopathy. CHCHD10 stabilizes mitochondrial crista ultrastructure and maintains its integrity. In patients with CHCHD10 mutations, there are abnormal mitochondrial crista structure, deficiencies of respiratory chain complexes, impaired mitochondrial respiration, and multiple mitochondrial DNA (mtDNA) deletions. Recently, CHCHD2 mutations are linked with autosomal dominant and sporadic Parkinson's disease (PD). The CHCHD2 is a multifunctional protein and plays roles in regulation of mitochondrial metabolism, synthesis of respiratory chain components, and modulation of cell apoptosis. With a better understanding of the pathophysiologic roles of CHCHD proteins, they may be potential novel therapeutic targets for human neurodegenerative diseases.
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PMID:Mitochondrial CHCHD-Containing Proteins: Physiologic Functions and Link with Neurodegenerative Diseases. 2771 1


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