Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the cause of dopaminergic cell death in Parkinson's disease is still poorly understood, there is accumulating evidence suggesting that metal ions can be involved in the processes. We investigated the effect of manganese on cell death and DNA damage in PC12 cells treated with dopamine. Mn(II) enhanced cell death induced by dopamine. Mn(II) also increased the 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) contents of DNA in PC12 cells treated with dopamine. To clarify the mechanism of cellular DNA damage, we investigated DNA damage induced by dopamine and Mn(II) using (32)P-labeled DNA fragments. Mn(II) enhanced Cu(II)-dependent DNA damage by dopamine. The Mn(II)-enhanced DNA damage was greatly increased by NADH. Piperidine and formamidopyrimidine-DNA glycosylase treatment induced cleavage sites mainly at T and G of the 5'-TG-3' sequence, respectively. Bathocuproine, a Cu(I) chelator, and catalase inhibited the DNA damage. Oxygen consumption and UV-visible spectroscopic measurements showed that Mn(II) enhanced autoxidation of dopamine with H(2)O(2) formation. These results suggest that reactive species derived from the reaction of H(2)O(2) with Cu(I) participates in Mn(II)-enhanced DNA damage by dopamine plus Cu(II). Therefore, it is concluded that oxidative DNA damage induced by dopamine in the presence of Mn(II), NADH, and Cu(II) is possibly linked to the degeneration of dopaminergic neurons.
 ...
PMID:Mechanism for manganese enhancement of dopamine-induced oxidative DNA damage and neuronal cell death. 1689 95

The contribution of mitochondria to the manifestation of disease is ascribed largely to the production of reactive oxygen species (ROS), which are obligatory by-products of aerobiosis. Studies using isolated mitochondria have revealed multiple potential sites and circumstances of ROS production but the relevance of these to in situ conditions is limited. In this article, we focus on bioenergetic factors that promote ROS generation at physiologically relevant sites in mitochondria. Emphasis is given to ROS generation by complex I--the first component of the respiratory chain--and to how the NADH:NAD+ ratio regulates ROS formation. Complex I is a physiologically and pathologically relevant ROS-forming site that is important not only in normal mitochondrial energy production but also in the pathogenesis of Parkinson's disease, which is the second most common neurodegenerative disease.
 ...
PMID:Bioenergetics and the formation of mitochondrial reactive oxygen species. 1705 27

The Parkinsonian syndrome induced by pesticides is associated with the impairment of mitochondrial function. Toxicants that inhibit selectively NADH-dehydrogenase activity, as rotenone or pyridaben, also show a selective inhibition of O2 uptake and respiratory control in rat brain mitochondria in the presence of NAD-dependent substrates. The IC50 of rotenone and pyridaben for complex I inhibition were in the range 1.7-2.2 microM. The determination of NADH-cytochrome c reductase, succinate-cytochrome c reductase and cytochrome oxidase activities in rat brain submitochondrial showed again the selective inhibition of Complex I by rotenone and pyridaben, whereas paraquat produced a non-selective inhibition affecting all the respiratory chain complexes. In rat brain mitochondria, rotenone and pyridaben markedly decreased mtNOS functional activity with NAD-dependent substrates but not when the substrate was succinate. This observation suggest than mtNOS activity is regulated by the activity of complex I. This regulation and the role of mitochondrial NO diffusion as a signal for mitochondrial biogenesis could have a role in the etiopathology of Parkinson's disease.
 ...
PMID:Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome. 1712 63

Mitochondrial Complex I (NADH Coenzyme Q oxidoreductase) is the least understood of respiratory complexes. In this review we emphasize some novel findings on this enzyme that are of relevance to the pathogenesis of neurodegenerative diseases. Besides Coenzyme Q (CoQ), also oxygen may be an electron acceptor from the enzyme, with generation of superoxide radical in the mitochondrial matrix. The site of superoxide generation is debated: we present evidence based on the rational use of several inhibitors that the one-electron donor to oxygen is an iron-sulphur cluster, presumably N2. On this assumption we present a novel mechanism of electron transfer to the acceptor, CoQ. Strong evidence is accumulating that electron transfer from Complex I to Complex III via CoQ is not performed by operation of the CoQ pool but by direct channelling within a super-complex including Complex I, Complex III and bound CoQ. Besides structural evidence of a Complex I -Complex III aggregate obtained by native electrophoresis, we have obtained kinetic evidence based on metabolic flux analysis, demonstrating that Complexes I and III behave as an individual enzyme. Quantitative and qualitative changes of phospholipids, including peroxidation, may affect the supercomplex formation. Complex I is deeply involved in pathological changes, including neurodegeneration. Maternally inherited mutations in mitochondrial DNA genes encoding for Complex I subunits are at the basis of Leber's Hereditary Optic Neuropathy; a decrease of electron transfer in the complex, due to the mutations, is not sufficient per se to explain the clinical phenotype, and other factors including proton translocation and oxygen radical generation have been considered of importance. Complex I changes are also involved in more common neurological diseases of the adult and old ages. In this review we discuss Parkinson's disease, where the pathogenic involvement of Complex I is better understood; the accumulated evidence on the mode of action of Complex I inhibitors and their effect on oxygen radical generation is discussed in terms of the aetiology and pathogenesis of the disease.
 ...
PMID:Mitochondrial Complex I: structure, function, and implications in neurodegeneration. 1727 29

As with chromosomal DNA, the mitochondrial DNA (mtDNA) can contain mutations that are highly pathogenic . In fact, many diseases of the central nervous system are known to be caused by mutations in mtDNA. Dysfunction of the mitochondrial Respiratory Chain (RC) has been shown in patients with neurological disease including Alzheimer's disease (AD), Parkinson's disease (PD) and Multiple sclerosis (MS). MS is a demyelinating disease of central nervous system characterized by morphological hallmarks of inflammation, demyelination and axonal loss. Considering this importance, we decided to investigate several highly mutative parts of mtDNA for point mutations as MT-LTI (tRNA(Leucine1(UUA/G))), MT-NDI (NADH Dehydrogenase subunit 1), MT-COII (Cytochrome c oxidase subunit II), MT-TK (tRNA(Lysine)), MT-ATP8 (ATP synthase subunit F0 8) and MT-ATP6 (ATP synthase subunit F0 6) in 20 Iranian MS patients and 80 age-matched control subjects by PCR and automated DNA sequencing to evaluate any probable point mutations. Our results revealed that 15 (75%) out of 20 MS patients had point mutations. Some of point mutations were newly found in this study. This study suggested that point mutation occurred in mtDNA might be involved in pathogenesis of MS.
 ...
PMID:Investigation on mitochondrial tRNA(Leu/Lys), NDI and ATPase 6/8 in Iranian multiple sclerosis patients. 1761 38

Nitroxyl radicals are important antioxidants that have been used to protect animal tissues from oxidative damage. Their reaction with hydroxyl radical ((*)OH) is generally accepted to be the mechanism of antioxidant function. However, the direct interaction of nitroxyl radicals with (*)OH does not always provide a satisfactory explanation in various pH, because the concentration of hydrogen ion may affect the generation of secondary (*)OH-derived radicals. In the present study, it was confirmed that the reaction between 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) and (*)OH generated TEMPOL-hydroxylamine, 4-oxo-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPON) and TEMPON-hydroxylamine using HPLC coupled with electrochemical detection. In the absence of NADH, TEMPOL-H may be generated by the reaction with secondary (*)OH-derived radicals in acidic condition. In the presence of NADH, a large proportion of the non-paramagnetic products was TEMPOL-H. Finally, it was clarified that TEMPOL-H was generated during dopamine metabolism, which is believed to be one of the (*)OH sources in pathological processes such as Parkinson's disease.
 ...
PMID:Formation of TEMPOL-hydroxylamine during reaction between TEMPOL and hydroxyl radical: HPLC/ECD study. 1848 14

Mitochondrial Complex I [NADH Coenzyme Q (CoQ) oxidoreductase] is the least understood of respiratory complexes. In this review we emphasize some novel findings on this enzyme that are of relevance to the pathogenesis of neurodegenerative diseases. Besides CoQ, also oxygen may be an electron acceptor from the enzyme, with generation of superoxide radical in the mitochondrial matrix. The site of superoxide generation is debated: we present evidence based on the rational use of several inhibitors that the one-electron donor to oxygen is an iron-sulphur cluster, presumably N2. On this assumption we present a novel mechanism of electron transfer to the acceptor, CoQ. Complex I is deeply involved in pathological changes, including neurodegeneration. Complex I changes are involved in common neurological diseases of the adult and old ages. Mitochondrial cytopathies due to mutations of either nuclear or mitochondrial DNA may represent a useful model of neurodegeneration. In this review we discuss Parkinson's disease, where the pathogenic involvement of Complex I is better understood; the accumulated evidence on the mode of action of Complex I inhibitors and their effect on oxygen radical generation is discussed in terms of the aetiology and pathogenesis of the disease.
 ...
PMID:Generation of reactive oxygen species by mitochondrial complex I: implications in neurodegeneration. 1853 5

NADH:ubiquinone oxidoreductase (complex I) is an entry point for electrons into the respiratory chain in many eukaryotes. It couples NADH oxidation and ubiquinone reduction to proton translocation across the mitochondrial inner membrane. Because complex I deficiencies occur in a wide range of neuromuscular diseases, including Parkinson's disease, there is a clear need for model eukaryotic systems to facilitate structural, functional and mutational studies. In the present study, we describe the purification and characterization of the complexes I from two yeast species, Pichia pastoris and Pichia angusta. They are obligate aerobes which grow to very high cell densities on simple medium, as yeast-like, spheroidal cells. Both Pichia enzymes catalyse inhibitor-sensitive NADH:ubiquinone oxidoreduction, display EPR spectra which match closely to those from other eukaryotic complexes I, and show patterns characteristic of complex I in SDS/PAGE analysis. Mass spectrometry was used to identify several canonical complex I subunits. Purified P. pastoris complex I has a particularly high specific activity, and incorporating it into liposomes demonstrates that NADH oxidation is coupled to the generation of a protonmotive force. Interestingly, the rate of NADH-induced superoxide production by the Pichia enzymes is more than twice as high as that of the Bos taurus enzyme. Our results both resolve previous disagreement about whether Pichia species encode complex I, furthering understanding of the evolution of complex I within dikarya, and they provide two new, robust and highly active model systems for study of the structure and catalytic mechanism of eukaryotic complexes I.
 ...
PMID:The respiratory complexes I from the mitochondria of two Pichia species. 1945 85

Mitochondrial metabolism is a highly orchestrated phenomenon in which many enzyme systems cooperate in a variety of pathways to dictate cellular fate. As well as its vital role in cellular energy metabolism (ATP production), mitochondria are powerful organelles that regulate reactive oxygen species production, NAD+/NADH ratio and programmed cell death. In addition, mitochondrial abnormalities have been well recognized to contribute to degenerative diseases, like Parkinson's disease (PD). Particularly a deficiency in the mitochondrial respiratory chain complex I and cristae disruption have been consistently described in PD. Moreover, the products of PD-familial genes, including alpha-synuclein, Parkin, PINK1, DJ-1, LRRK2 and HTR2A, were shown to localize to the mitochondria under certain conditions. It seems that PD has a mitochondrial component so events that would modulate normal mitochondrial functions may compromise neuronal survival. However, it remains an open question whether alterations of these pathways lead to different aspects of PD or whether they converge at a point that is the common denominator of PD pathogenesis. In this review we will focus on mitochondrial metabolic control and its implications on sirtuins activation, microtubule dynamics and autophagic-lysosomal pathway. We will address mitochondrial metabolism modulation as a new promising therapeutic tool for PD.
 ...
PMID:Mitochondrial metabolism modulation: a new therapeutic approach for Parkinson's disease. 2020 21

Disorders of the function of the tyrosine hydroxylase play an important role in the occurrence of the Parkinson syndrome. The enzyme that catalyses the first, rate-limiting step in the biosynthesis to dopamine requires the cofactor tetrahydrobiopterin. This compound supplies the reduction equivalent for activation of molecular oxygen. Binding of the cofactor to the enzyme is affected by phosphorylation or dephosphorylation of the enzyme protein and, thereby, influences the activity. Nerve and chromaffin cells that synthesize dopamine, noradrenaline and serotonin are able to synthesize the cofactor tetrahydrobiopterin de novo from guanosine-triphosphate as a precursor. In patients suffering from Parkinson's disease a remarkable decrease in biopterin content was found in the brain. The function of the dopaminergic system was studied with an experimental Parkinson model. The antimetabolite 6-aminonicotinamide induces a dopamine deficit in the striatum with a significant slowdown in the utilization of this transmitter. The abolition of the 6-aminonicotinamide-induced muscular rigidity by l-DOPA and dopamine agonists implies that the antimetabolite produces a Parkinson-like syndrome in rats. There are reports on the molecular basis of this effect which are also important for understanding possible disturbances of the synthesis of biopterins. The effector 6-aminonicotinamide-adenine-dinucleotide-phosphate (6-ANADP), which blocks the pentose phosphate pathway, is formed by an enzymatic neurotoxic synthesis. The clonal cell line PC-12 was used to study the molecular basis of the disturbances occurring in the dopaminergic system. These cells contain all the enzymes for catecholamine synthesis, including those for the synthesis of the cofactor tetrahydrobiopterin. Addition of 6-aminonicotinamide to the culture medium resulted in the synthesis of the neurotoxic agent, 6-ANADP, by a glycohydrolase localized in the endoplasmic reticulum. The synthesis of biopterin was depressed after application of 6-aminonicotinamide. The decrease of intracellular tetrahydrobiopterin and total biopterin resulted in reduced DOPA production. The decreased content of biopterin cofactor synthesis was compensated for by the addition of the precursor sepiapterin, indicating that the NADPH-dependent reductases in biopterin synthesis were not inhibited by the antimetabolic nucleotide 6-ANADP. DOPA production was not fully normalized by sepiapterin. Addition of NADH to the medium resulted in a further increase of DOPA production, probably by activation of the recycling pathway. The first step in the synthesis of biopterin from GTP to 7,8-neopterin-triphosphate seems to be particularly sensitive to the action of exogenous neurotoxins. A further sensitive site of action in synthesis to the cofactor BH(4) concerns the function of the dihydropteridin-reductase, which recycles qBH(2) to BH(4). Neurotoxin-induced impairment of biopterin synthesis is probably a pathogenetically important disorder at the initial stage of Parkinson's disease.
 ...
PMID:Neurotoxin-induced impairment of biopterin synthesis and function: Initial stage of a Parkinson-like dopamine deficiency syndrome. 2050 23


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>