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)

Postmortem changes in mitochondrial respiratory enzymes (Complex I-IV and NAD(+)-linked dehydrogenases in the TCA cycle) were studied in mouse brains and human frontal lobes. In mouse brains, activities of the enzymes studied were generally stable for as long as 12 h after cervical dislocation, except for the alpha-ketoglutarate dehydrogenase complex and NADP(+)-linked isocitrate dehydrogenase. In human frontal cortices, only NADH-ubiquinone reductase (Complex I) activity showed significant negative correlation with the duration between the patient's death and the freezing of the brain. No correlations between the activities of the enzymes studied and the age of the patients were noted. As most of our patients were 50 years of age or above, absence of the correlation cannot be extended to younger patients. From our observation, it was felt that analyses of these mitochondrial enzymes in human autopsy brains would give meaningful data. Preliminary observation in Parkinson's disease revealed a small but a significant decrease in the activity of Complex III in the striatum as compared with the control. Although, significance of our observation is not yet known, further studies on this line appear to be important to elucidate pathogenesis of Parkinson's disease.
 ...
PMID:Postmortem changes in mitochondrial respiratory enzymes in brain and a preliminary observation in Parkinson's disease. 235 87

We discuss the etiology and pathogenesis of Parkinson's disease (PD). Our group and others have found a decrease in complex I of the mitochondrial electron transfer complex in the substantia nigra of patients with PD; in addition, we reported loss of the alpha-ketoglutarate dehydrogenase complex (KGDHC) in the substantia nigra. Dual loss of complex I and the KGDHC will deleteriously affect the electron transport and ATP synthesis; we believe that energy crisis is the most important mechanism of nigral cell death in PD. Oxidative stress has also been implicated as an important contributor to nigral cell death in PD, but we believe that oxidative stress is a secondary phenomenon to respiratory failure, because respiratory failure will increase oxygen free-radical formation and consume glutathione. The primary cause of mitochondrial respiratory failure has not been elucidated yet, but additive effect of environmental neurotoxins in genetically predisposed persons appears to be the most likely possibility.
 ...
PMID:Role of mitochondria in the etiology and pathogenesis of Parkinson's disease. 759 19

Defects in complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH) occur in the substantia nigra in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) are implicated in the cause of PD as endogenous toxins and are inhibitors of complex I. However, their effects on alpha-KGDH and other mitochondrial non-respiratory chain enzymes are unknown. We have examined the effects of six isoquinoline derivatives (isoquinoline, N-methylisoquinolinium, N-n-propylisoquinolinium, 1,2,3,4-tetrahydroisoquinoline, N-methyl-1,2,3,4-tetrahydroisoquinoline and salsolinol) and MPP+ on the activities of alpha-KGDH, citrate synthase (CS) and glutamate dehydrogenase (GDH) in mitochondrial fragments from rat forebrain. None of the compounds examined had any effect on CS or GDH activity. In contrast, all isoquinoline derivatives investigated and MPP+ inhibited alpha-KGDH activity in a concentration-dependent manner with IC50s ranging from 2.0 to 18.9 mM. MPP+ was previously shown to inhibit alpha-KGDH, but this is the first report of inhibition of alpha-KGDH by isoquinoline derivatives. These findings may represent an additional mechanism contributing to mitochondrial dysfunction and cell death in Parkinson's disease.
 ...
PMID:Inhibition of alpha-ketoglutarate dehydrogenase by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 766 87

We report an immunohistochemical study of the mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC) in the substantia nigra in Parkinson's disease. The KGDHC, the three enzyme complex catalyzing the oxidation of alpha-ketoglutarate to succinate through succinic semialdehyde, is the rate-regulating enzyme of the TCA cycle. The mitochondrial toxin, MPP+, inhibits not only complex I but also the KGDHC. Therefore, we investigated this enzyme complex in Parkinson's disease. In the control patients (n = 6), the immunostaining of the melanized nigral neurons was generally uniform; most of the melanized neurons showed good immunostaining with some neurons showing somewhat reduced staining. In Parkinson's disease (n = 9), many melanized neurons showed reduced immunostaining for the KGDHC, and those neurons were more frequently seen in the lateral one-third of substantia nigra. The decrease in the immunostaining for the KGDHC correlated roughly with the severity of degeneration. The KGDHC is more vulnerable to degeneration than complex II, III, and IV as noted in our previous immunohistochemical study. Even if secondary, the loss may play a role in the progression of the disease.
 ...
PMID:An immunohistochemical study on alpha-ketoglutarate dehydrogenase complex in Parkinson's disease. 810

Nigral cell death in Parkinson's disease is associated with decreased reduced glutathione (GSH) levels, impaired complex I activity and inhibition of alpha-ketoglutarate dehydrogenase (alpha-KGDH) in substantia nigra. Thioctic acid exerts antioxidant activity through a thiol-disulphide redox couple and is an essential cofactor for alpha-KGDH. However, it is not known whether or not thioctic acid enters basal ganglia or exerts beneficial effects in Parkinson's disease. As a global measure of altered cerebral function, the effect of R- and S-thioctic acid on 14C-2-deoxyglucose (14C-2DG) incorporation was investigated in rats. Rats were treated with either R- or S-thioctic acid (50 mg/kg IP) or 0.9% saline acutely or for 5 days and 14C-2DG incorporation in basal ganglia was assessed. Following acute administration, R- but not S-thioctic acid caused an overall increase in 14C-2DG incorporation that was significant in both substantia nigra zona compacta and zona reticulata. R-thioctic acid also increased the incorporation of 14C-2DG in the medial forebrain bundle, thalamus, and red nucleus. S-thioctic acid decreased 14C-2DG incorporation in the subthalamic nucleus, but increased it in the red nucleus. Following repeated administration, R-thioctic acid no longer increased 14C-2DG incorporation in either zona compacta or zona reticulata of substantia nigra. However, both R- and S-thioctic acid now decreased 14C-2DG incorporation in the subthalamic nucleus. The data suggest that thioctic acid does enter the brain can alter neuronal activity in areas of the basal ganglia intimately associated with the motor deficits exhibited in Parkinson's disease.
 ...
PMID:The isomers of thioctic acid alter C-deoxyglucose incorporation in rat basal ganglia. 865 49

We review the recent progress in the research of the etiology, pathogenesis and treatment of Parkinson's disease. It has been postulated that mitochondrial respiratory failure and oxidative stress are two major contributors to nigral cell death in Parkinson's disease. Loss of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase complex in the substantia nigra has been reported. Evidence to indicate oxidative stress includes a high dopamine content, increase in superoxide dismutase activities, increase in iron, and decrease in glutathione in the substantia nigra. The question posed is which one occurs first. We believe mitochondrial respiratory failure occurs first, because slowing down of the electron transport induces an increase in the formation of activated oxygen species. The primary cause of Parkinson's disease is still unknown, but we believe the interaction of environmental toxins and genetic predispositions is important. In this respect, molecular genetic studies on familial Parkinson's disease are very important.
 ...
PMID:Parkinson's disease: from etiology to treatment. 877 62

In substantia nigra from patients with Parkinson's disease, there are decreased levels of reduced glutathione (GSH) and diminished activities of mitochondrial complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH), along with increased activity of superoxide dismutase (SOD). However, the interrelationship among these events is uncertain. We now report the effect of decreased brain GSH levels on SOD and mitochondrial respiratory enzyme activity in rat brain. In addition, we have investigated the ability of thioctic acid, an endogenous antioxidant, to alter these parameters. Unilateral or bilateral intracerebroventricular (ICV) administration of buthionine sulphoximine (BSO; 1 x 3.2 mg or 2 x 1.6 mg) over a 48-hr period reduced cortical GSH by 55-70%. There was no change in the activity of complex I, II/III, or IV or of citrate synthase in cortex. Similarly, there was no alteration of mitochondrial or cytosolic SOD activity. Thioctic acid (50 or 100 mg/kg IP) alone had no effect on cortical GSH levels in control animals and did not reverse the decrease in GSH levels produced by unilateral or bilateral ICV BSO administration. Thioctic acid (50 or 100 mg/kg IP) had no overall effect on complex I, II/III, or IV or on citrate synthase activity in control animals. Thioctic acid also did not alter cortical mitochondrial respiratory enzyme activity in BSO-treated rats. At the lower dose, thioctic acid tended to increase mitochondrial and cytosolic SOD activity in control animals and in BSO-treated rats. However, at the higher dose, thioctic acid tended to decrease mitochondrial SOD activity. Overall, there was no consistent effect of thioctic acid (50 or 100 mg/kg IP) on SOD activity in control or BSO-treated animals. This study shows that BSO-induced glutathione deficiency does not lead to alterations in mitochondrial respiratory enzyme activity or to changes in SOD activity. GSH depletion in Parkinson's disease therefore may not account for the alterations occurring in complex I and mitochondrial SOD in substantia nigra. Thioctic acid did not alter brain GSH levels or mitochondrial function. Interestingly, however, it did produce some alterations in SOD activity, which may reflect either its antioxidant activity or its ability to act as a thiol-disulphide redox couple.
 ...
PMID:Mitochondrial respiratory enzyme function and superoxide dismutase activity following brain glutathione depletion in the rat. 898 27

Dihydrolipoamide succinyltransferase (E2, EC 2.3.1.61, chromosome 14q24.2-3) is a specific subunit of human alpha-ketoglutarate dehydrogenase complex (KGDHC). A biallelic intragenic polymorphism was identified in E2 gene of KGDHC. It was a single nucleotide substitution between G (in allele 1) and A (in allele 2) at the position that does not change amino acid code. Using this intragenic polymorphism as a marker, we investigated the association between this gene and Parkinson's disease. Frequencies of the genotypes that carry allele 2 were significantly higher in the Parkinson's disease group than in the control group. The results indicated that a genetic variant of the E2 gene itself or in close proximity to the gene constitutes one of the genetic risk factors for Parkinson's disease.
 ...
PMID:Association between the gene encoding the E2 subunit of the alpha-ketoglutarate dehydrogenase complex and Parkinson's disease. 945 Jul 78

The cause of neurodegeneration in Parkinson's disease (PD) remains unknown. However, isoquinoline derivatives structurally related to the selective dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite, 1-methyl-4-phenylpyridinim (MPP+), have emerged as candidate endogenous neurotoxins causing nigral cell death in Parkinson's disease. Isoquinoline derivatives are widely distributed in the environment, being present in many plants and foodstuffs, and readily cross the blood-brain barrier. These compounds occur naturally in human brain where they are synthesized by non-enzymatic condensation of biogenic amines (e.g. catecholamines and phenylethylamine) with aldehydes, and are metabolized by cytochrome P450s and N-methyltransferases. In addition, isoquinoline derivatives are oxidized by monoamine oxidases to produce isoquinolinium cations with the concomitant generation of reactive oxygen species. Neutral and quaternary isoquinoline derivatives accumulate in dopaminergic nerve terminals via the dopamine re-uptake system, for which they have moderate to poor affinity as substrates. Several isoquinoline derivatives are selective and more potent inhibitors of NADH ubiquinone reductase (complex I) and alpha-ketoglutarate dehydrogenase activity in mitochondrial fragments than MPP+, and lipophilicity appears to be important for complex I inhibition by isoquinoline derivatives. However, compared with MPP+, isoquinoline derivatives are selective but less potent inhibitors of NADH-linked respiration in intact mitochondria, and this appears to be a consequence of their rate-limiting ability to cross mitochondrial membranes. Although both active and passive processes are involved in the accumulation of isoquinoline derivatives in mitochondria, inhibition of respiration is determined by steric rather than electrostatic properties. Compared with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or MPP+, isoquinoline derivatives show selective but relatively weak toxicity to dopamine-containing cells in culture and following systemic or intracerebral administration to experimental animals, which appears to be a consequence of poor sequestration of isoquinoline derivatives by mitochondria and by dopamine-containing neurones. In conclusion, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-like cytotoxic characteristics of isoquinoline derivatives and the endogenous/environmental presence of these compounds make it conceivable that high concentrations of and/or prolonged exposure to isoquinoline derivatives might cause neurodegeneration and Parkinson's disease in humans.
 ...
PMID:Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson's disease. 977 2

Mitochondrial membrane potential (delta psi(m)) was determined in intact isolated nerve terminals using the membrane potential-sensitive probe JC-1. Oxidative stress induced by H2O2 (0.1-1 mM) caused only a minor decrease in delta psi(m). When complex I of the respiratory chain was inhibited by rotenone (2 microM), delta psi(m) was unaltered, but on subsequent addition of H2O2, delta psi(m) started to decrease and collapsed during incubation with 0.5 mM H2O2 for 12 min. The ATP level and [ATP]/[ADP] ratio were greatly reduced in the simultaneous presence of rotenone and H2O2. H2O2 also induced a marked reduction in delta psi(m) when added after oligomycin (10 microM), an inhibitor of F0F1-ATPase. H2O2 (0.1 or 0.5 mM) inhibited alpha-ketoglutarate dehydrogenase and decreased the steady-state NAD(P)H level in nerve terminals. It is concluded that there are at least two factors that determine delta psi(m) in the presence of H2O2: (a) The NADH level reduced owing to inhibition of alpha-ketoglutarate dehydrogenase is insufficient to ensure an optimal rate of respiration, which is reflected in a fall of delta psi(m) when the F0F1-ATPase is not functional. (b) The greatly reduced ATP level in the presence of rotenone and H2O2 prevents maintenance of delta psi(m) by F0F1-ATPase. The results indicate that to maintain delta psi(m) in the nerve terminal during H2O2-induced oxidative stress, both complex I and F0F1-ATPase must be functional. Collapse of delta psi(m) could be a critical event in neuronal injury in ischemia or Parkinson's disease when H2O2 is generated in excess and complex I of the respiratory chain is simultaneously impaired.
 ...
PMID:Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals: inhibition of alpha-ketoglutarate dehydrogenase. 1038 74


1 2 3 Next >>