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: EC:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson disease is a neurodegenerative disorder of aging characterized by a selective and progressive loss of dopaminergic neurons within the substantia nigra. The diagnosis of the disease is made when neuronal cell loss exceeds 50 p. cent indicating that the degenerative process started well before the onset of the first clinical symptoms. Three populations of dopaminergic neurons seem to coexist in the substantia nigra of parkinsonian patients; (1) senescent neurons that are still spared by the pathological process; (2) sick neurons exhibiting generally a preserved morphology but showing evidence of biochemical and metabolic abnormalities; (3) neurons which have entered into a final state of agony and exhibit the hallmarks of apoptosis, a controlled form of cell death that requires the activation of a particular type of proteases, caspases. In the inherited forms of the disease that are caused by mutations of genes encoding the Parkin, alpha-synuclein and UCHL-1 proteins, the degenerative process results from the dysfunction of an enzymatic complex of proteolysis, the proteasome. This probably leads to the intracellular accumulation of abnormal proteins that become deleterious for dopaminergic neurons. In the sporadic forms of the disease that are the most frequent, causes of the cell demise remain still unknown but neurodegeneration might also result from a decreased activity of the proteasome. A defect in the detoxification of reactive oxygen species or an energy failure caused by inhibition of the mitochondrial respiratory chain, at the complex I level, are other hypothesis that are frequently mentioned. Finally, activated glial cells (astrocytes and microglia) located around the degenerating dopaminergic neurons might also intervene in the mechanism of degeneration by perpetuating or even amplifying the primary neuronal insult. Proinflammatory cytokines acting on cell death membrane receptors and diffusable messengers such as nitric oxide could be part of this process.
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PMID:[Parkinson's disease: cell death mechanisms] 1269 Mar 12

Parkinson disease is a neurodegenerative disorder of aging characterized by a selective and progressive loss of dopaminergic neurons within the substantia nigra. The diagnosis of the disease is made when neuronal cell loss exceeds 50 p. 100 indicating that the degenerative process started well before the onset of the first clinical symptoms. Three populations of dopaminergic neurons seem to coexist in the substantia nigra of parkinsonian patients; (1) senescent neurons that are still spared by the pathological process; (2) sick neurons exhibiting generally a preserved morphology but showing evidence of biochemical and metabolic abnormalities; (3) neurons which have entered into a final state of agony and exhibit the hallmarks of apoptosis, a controlled form of cell death that requires the activation of a particular type of proteases, caspases. In the inherited forms of the disease that are caused by mutations of genes encoding the Parkin, alpha-synuclein and UCHL-1 proteins, the degenerative process results from the dysfunction of an enzymatic complex of proteolysis, the proteasome. This probably leads to the intracellular accumulation of abnormal proteins that become deleterious for dopaminergic neurons. In the sporadic forms of the disease that are the most frequent, causes of the cell demise remain still unknown but neurodegeneration might also result from a decreased activity of the proteasome. A defect in the detoxification of reactive oxygen species or an energy failure caused by inhibition of the mitochondrial respiratory chain, at the complex I level, are other hypothesis that are frequently mentioned. Finally, activated glial cells (astrocytes and microglia) located around the degenerating dopaminergic neurons might also intervene in the mechanism of degeneration by perpetuating or even amplifying the primary neuronal insult. Proinflammatory cytokines acting on cell death membrane receptors and diffusable messengers such as nitric oxide could be part of this process.
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PMID:[Parkinson disease: mechanisms of cell death]. 1269 Jun 61

We report a review on progress in the etiology and pathogenesis of Parkinson's disease (PD). We also report the long-term prognosis of PD patients seen in our clinic. Modern research on the pathogenesis started after the discovery of MPTP. We found inhibition of mitochondrial complex I by MPTP and MPP+. Mitochondrial respiratory failure induces oxidative damage to high molecular weight substances. Both mitochondrial failure and oxidative stress are important triggers of apoptosis. We found TUNEL positive nigral neurons in PD patients suggesting involvement of apoptosis in the pathogenesis. Interaction of genetic risk factors and environmental neurotoxins has been implicated in the etiology of PD. While we were investigating MnSOD gene polymorphism in PD patients, we found a young onset autosomal recessive PD family that was linked to the MnSOD locus. Subsequent linkage analysis on 13 families of young onset autosomal recessive families disclosed the linkage of this disease to the telomeric region of the long arm of chromosome 6 (6q25.2-27). Then we were lucky enough to find a patient who had a deletion of one of the microsatellite markers (D6S305) that we were using in the linkage analysis. We thought this marker might be located within the disease gene and this was the case. We screened the Keio BAC library with this marker, and eventually we cloned a novel gene encompassing 1.4 Mb; we named it parkin. The coding region consisted of 1,395 base pairs. The parkin protein had an unique sequence in that there was a 30% homology in the amino terminal region and two RING-finger motives on the carboxy terminal side. This unique structure suggested that the parkin protein was related to the ubiquitin-proteasome system. Parkin protein turned out to be an ubiquitin-protein ligase. Numbers of parkin-interacting proteins were reported in the literature and accumulation of parkin-substrates is likely to be the cause for the nigral neuronal death in this familial PD. Regarding the prognosis of PD, we analyzed the patients who visited our clinic from January 1, 1989 to December 31, 2002. The total of patients recruited was 1,772. The average age of onset was 57.2 years. Mean levodopa dose at the final examination was 479 mg/day. The most common initial symptom was tremor which was seen in 51% of the patients. Total percentage of patients who had tremor during the course of the disease was 75%. Long-term prognosis was evaluated on a subgroup of the patients who visited our clinic within 5 years from the onset and Hoehn and Yahr stage III or less when first seen. Analysis was done by the Kaplan-Meier survival curve. Percentages of patients who reached Hoehn and Yahr III 5, 10, and 15 years after the onset were 24%, 46%, and 65%, respectively. Percentages of patients who developed wearing off fluctuations were 5, 10, and 15 years after the start of levodopa were 18%, 46%, and 55%, respectively. Overall mortality on the total investigated patients was 7.9%. When compared to the age at death of Japanese population, mortality of men PD patients became very close to that of the general population in the year 2003. However, that in women PD patients showed significantly shorter survival compared to Japanese female population. Average ages of onset and the death were essentially similar between men and women PD patients. Survival curves to reach stage III and wearing off showed slightly but significantly faster time courses for women compared to those of men. This was an unexpected observation and its mechanism was discussed. It is our conclusion that overall prognosis of PD patients is improving and both patients and treating physicians should take an optimistic attitude to the disease.
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PMID:[Progress in the basic and clinical aspects of Parkinson's disease]. 1565 Dec 81

Mutations in the gene encoding alpha-synuclein (asyn) causes autosomal-dominant, in the parkin gene autosomal-recessive forms of Parkinson's disease (PD). The pathophysiology of PD is poorly understood, even though published evidence suggests a role for mitochondria in the pathogenesis. To gain insight into the influence of asyn and parkin on mitochondrial integrity and function, we have generated several mono-mutant mouse lines expressing doubly mutated human asyn (hm(2)asyn) under the control of two different promoters, or a targeted deletion of Parkin (Parkin-Exon3-knockout). Both mouse lines were crossed to generate the double-mutant. Here we compare the ultrastructure and functional properties of mitochondria in the substantia nigra (SN), the striatum, the cerebral cortex (Cx) and skeletal muscle of young (2-3 months) and aged (12-14 months) mono- and double-mutants mice. We observed severe genotype-, age- and region-dependent morphological alterations of mitochondria in neuronal somata. The number of structurally altered mitochondria was significantly increased in the SN of both double-mutants and in the Cx of one mono- and one double-mutant line. These alterations coincided with a reduced complex I capacity in the SN, but were neither accompanied by alterations in the number or the size of the mitochondria nor by leakage of cytochrome c, Smac/DIABLO or Omi/HtrA2. None of the transgenic animals developed any gross histopathological abnormalities or overt motor disabilities. Together our results provide compelling evidence that (i) both, asyn and parkin are relevant for mitochondrial integrity, (ii) the influence of these proteins on mitochondria are age- and tissue-specific and (iii) changes of mitochondrial morphology do not inevitably cause functional impairments.
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PMID:Mono- and double-mutant mouse models of Parkinson's disease display severe mitochondrial damage. 1741 59

Parkin, a ubiquitin ligase, is responsible for autosomal recessive juvenile parkinsonism (AR-JP). We identified parkin-associated endothelin receptor-like receptor (Pael-R) as a substrate of parkin, whose accumulation is thought to induce unfolded protein response (UPR) -mediated cell death, leading to dopaminergic neurodegeneration. To create an animal model of AR-JP, we generated parkin knockout/Pael-R transgenic (parkin-ko/Pael-R-tg) mice. parkin-ko/Pael-R-tg mice exhibited early and progressive loss of dopaminergic as well as noradrenergic neurons without formation of inclusion bodies, recapitulating the pathological features of AR-JP. Evidence of activation of UPR and up-regulation of dopamine and its metabolites were observed throughout the lifetime. Moreover, complex I activity of mitochondria isolated from parkin-ko/Pael-R-tg mice was significantly reduced later in life. These findings suggest that persistent induction of unfolded protein stress underlies chronic progressive catecholaminergic neuronal death, and that dysfunction of mitochondrial complex I and oxidative stress might be involved in the progression of Parkinson's disease. parkin-ko/Pael-R-tg mice represents an AR-JP mouse model displaying chronic and selective loss of catecholaminergic neurons.
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PMID:Pael-R transgenic mice crossed with parkin deficient mice displayed progressive and selective catecholaminergic neuronal loss. 1869 89

Parkinson's disease (PD), the most frequent movement disorder, is caused by the progressive loss of the dopamine neurons within the substantia nigra pars compacta (SNc) and the associated deficiency of the neurotransmitter dopamine in the striatum. Most cases of PD occur sporadically with unknown cause, but mutations in several genes have been linked to genetic forms of PD (alpha-synuclein, Parkin, DJ-1, PINK1, and LRRK2). These genes have provided exciting new avenues to study PD pathogenesis and the mechanisms underlying the selective dopaminergic neuron death in PD. Epidemiological studies in humans, as well as molecular studies in toxin-induced and genetic animal models of PD show that mitochondrial dysfunction is a defect occurring early in the pathogenesis of both sporadic and familial PD. Mitochondrial dynamics (fission, fusion, migration) is important for neurotransmission, synaptic maintenance and neuronal survival. Recent studies have shown that PINK1 and Parkin play crucial roles in the regulation of mitochondrial dynamics and function. Mutations in DJ-1 and Parkin render animals more susceptible to oxidative stress and mitochondrial toxins implicated in sporadic PD, lending support to the hypothesis that some PD cases may be caused by gene-environmental factor interactions. A small proportion of alpha-synuclein is imported into mitochondria, where it accumulates in the brains of PD patients and may impair respiratory complex I activity. Accumulation of clonal, somatic mitochondrial DNA deletions has been observed in the substantia nigra during aging and in PD, suggesting that mitochondrial DNA mutations in some instances may pre-dispose to dopamine neuron death by impairing respiration. Besides compromising cellular energy production, mitochondrial dysfunction is associated with the generation of oxidative stress, and dysfunctional mitochondria more readily mediate the induction of apoptosis, especially in the face of cellular stress. Collectively, the studies examined and summarized here reveal an important causal role for mitochondrial dysfunction in PD pathogenesis, and suggest that drugs and genetic approaches with the ability to modulate mitochondrial dynamics, function and biogenesis may have important clinical applications in the future treatment of PD.
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PMID:Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. 1930 5

Currently, only symptomatic therapy is available for Parkinson's disease. The zebrafish is a vertebrate animal model ideally suited for high throughput compound screening to identify disease-modifying compounds for Parkinson's disease. We have developed a zebrafish model for Parkin deficiency, the most commonly mutated gene in early onset Parkinson's disease. The zebrafish Parkin protein is 62% identical to its human counterpart with 78% identity in functionally relevant regions. The parkin gene is expressed throughout zebrafish development and ubiquitously in adult zebrafish tissue. Abrogation of Parkin activity leads to a significant decrease in the number of ascending dopaminergic neurons in the posterior tuberculum (homologous to the substantia nigra in humans), an effect enhanced by exposure to MPP+. Both light microscopic analysis and staining with the pan-neuronal marker HuC confirmed that this loss of dopaminergic neurons is not due to general impairment of brain development. Neither serotonergic nor motor neurons were affected, further emphasizing that the effect of parkin knockdown appears to be specific for dopaminergic neurons. Notably, parkin knockdown zebrafish embryos also develop specific reduction in the activity of the mitochondrial respiratory chain complex I, making this the first vertebrate model to share both important pathogenic mechanisms (i.e. complex I deficiency) and the pathological hallmark (i.e. dopaminergic cell loss) with human parkin-mutant patients. The zebrafish model is thus ideally suited for future drug screens and other studies investigating the functional mechanisms underlying neuronal cell death in early onset Parkinson's Disease. Additional electron microscopy studies revealed electron dense material in the t-tubules within the muscle tissue of parkin knockdown zebrafish. T-tubules are rich in L-type calcium channels, therefore our work might also provide a tentative link between genetically determined early onset Parkinson's disease and recent studies attributing an important role to these L-type calcium channels in late onset sporadic Parkinson's disease.
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PMID:Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio). 1943 22

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.
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PMID:Mitochondrial metabolism modulation: a new therapeutic approach for Parkinson's disease. 2020 21

It is clear from a striking convergence of human tissue studies, neurotoxin models, and genetic models that mitochondrial dysregulation plays a central pathogenic role in Parkinson's disease (PD) and related neurodegenerative conditions. Impaired mitochondrial quality could result from both increased damage and decreased ability to repair or clear damaged mitochondria. In particular, common deficits in mitochondrial respiratory chain function, oxidative stress, morphology/dynamics, and calcium handling capacities have been described in multiple PD model systems employing complex I inhibitors, 6-hydroxydopamine and molecular manipulation of Parkinsonian genes including alpha-synuclein, PTEN-induced kinase 1, Parkin, DJ-1, and, to a lesser extent, leucine rich repeat kinase 2. The most recent and exciting work implicates alterations in the regulation of macroautophagy and likely of selective mitophagic clearance of damaged mitochondria, although additional studies are needed to resolve some issues in this area. Future studies emphasizing the normal mitoprotective function(s) of proteins associated with recessive loss-of-function causes of familial PD, as well as compensatory mechanisms operating in their absence, may offer particularly valuable insights into strategies to enhance mitochondrial health.
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PMID:Mitochondrial dysfunction in Parkinson's disease. 2044 95

For decades, it has been presumed that mitochondrial dysfunction, in the form of impaired complex I activity, may contribute to the cause of Parkinson disease (PD). ( 1) The discovery that several gene mutations cause familial forms of PD ( 1) has led to a renewed enthusiasm for the mitochondrial hypothesis of PD, but this time from a quite distinct and, perhaps, more realistic angle. Among these genes, those that code for PTEN-induced kinase-1 (PINK1) ( 2) and for the E3-ubiquitin ligase Parkin ( 3) did attract major interest from mitochondriologists, in part, because both proteins interact with each other and apparently function, genetically, within the same molecular pathway to modulate mitochondrial dynamics in Drosophila. ( 4-6).
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PMID:PINK1 points Parkin to mitochondria. 2048 84


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