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)

Parkinson's disease (PD) is characterized by selective depletion of nigral dopamine (DA) neurons containing neuromelanin (NM), suggesting the involvement of NM in the pathogenesis. This study reports induction of apoptosis by NM in SH-SY5Y cells, whereas protease-K-treated NM, synthesized DA- and cysteinyl dopamine melanin showed much less cytotoxicity. Cell death was mediated by mitochondria-mediated apoptotic pathway, namely collapse of mitochondrial membrane potential, release of cytochrome c, and activation of caspase 3, but Bcl-2 over-expression did not suppress apoptosis. NM increased sulfhydryl content in mitochondria, and a major part of it was identified as GSH, whereas dopamine melanin significantly reduced sulfhydryl levels. Western blot analysis for protein-bound GSH demonstrated that only NM reduced S-glutathionylated proteins in mitochondria and dissociated macromolecular structure of complex I. Reactive oxygen and nitrogen species were required for the deglutathionylation by NM, which antioxidants reduced significantly with prevention of apoptosis. These results suggest that NM may be related to cell death of DA neurons in PD and aging through regulation of mitochondrial redox state and S-glutathionylation, for which NM-associated protein is absolutely required. The novel function of NM is discussed in relation to the pathogenesis of PD.
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PMID:Neuromelanin selectively induces apoptosis in dopaminergic SH-SY5Y cells by deglutathionylation in mitochondria: involvement of the protein and melanin component. 1839 61

Mitochondria have been implicated in the pathogenesis of several neurodegenerative disorders and, in particular, complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3) activity has been shown to be partially reduced in postmortem studies of the substantia nigra of Parkinson's disease patients. The present study examines the effect of partial inhibition of complex I activity on glutamate release from rat brain synaptosomes. Following a 40% inhibition of complex I activity with rotenone, it was found that Ca(2+)-independent release of glutamate increased from synaptosomes depolarized with 4-aminopyridine. Highest rates of glutamate release were found to occur between 60-90% complex I inhibition. A similar pattern of increase was shown to occur in synaptosomes depolarized with KCl. The increase in glutamate release was found to correlate to a significant decrease in ATP. Inhibition of complex I activity by 40% was also shown to cause a significant collapse in mitochondrial membrane potential (Deltapsi(m)). These results suggest that partial inhibition of complex I activity in in situ mitochondria is sufficient to significantly increase release of glutamate from the pre-synaptic nerve terminal. The relevance of these results in the context of excitotoxicity and the pathogenesis of neurodegenerative disorders is discussed.
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PMID:Partial inhibition of complex I activity increases Ca-independent glutamate release rates from depolarized synaptosomes. 1844 36

Kynurenic acid (KYNA), a tryptophan metabolite in the kynurenine pathway, is protective against various insults. However, the molecular mechanism of this protective effect has not been identified. In this study, we examined the protective effects of KYNA against 1-methyl-4-phenylpyridinium (MPP(+)), the best-characterized toxin inducing pathological changes resembling Parkinson's disease (PD), using SH-SY5Y and SK-N-SH human neuroblastoma cells. Pre-treatment of KYNA attenuated MPP(+)-induced neuronal cell death in SH-SY5Y and SK-N-SH cells. MPP(+)-induced cell death was preceded by increases in Bax expression and mitochondrial dysfunction, such as collapse of mitochondrial membrane potential (DeltaPsi(m)), release of cytochrome c from mitochondria into the cytoplasm, and increases in caspase-9/-3 activities. KYNA effectively inhibited all of these mitochondrial apoptotic processes. Our results indicate that KYNA plays a protective role by down-regulating Bax expression and maintaining mitochondrial function in MPP(+)-induced neuronal cell death, and suggest that KYNA may have therapeutic potential in PD.
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PMID:Kynurenic acid attenuates MPP(+)-induced dopaminergic neuronal cell death via a Bax-mediated mitochondrial pathway. 1846 30

Freezing of gait (FOG) in Parkinson's disease (PD) is defined as a sudden inability to maintain effective stepping movements. However, its pathophysiology remains unclear. The objectives are: (1) To assess the contribution of both spatial (walking speed, stride length) and temporal parameters (cadence, stride time) and their coefficients of variation to the genesis of FOG in PD. (2) To evaluate whether and how externally imposed modifications of self-determined gait would elicit FOG. We included ten patients with advanced PD, and with daily off drug FOG episodes. We focused on walking in an open runway. For each subject, we manipulated gait by externally imposing four changes in walking speed and four changes in cadence. FOG episodes, often with a long duration of more than 5-s, were observed mostly under conditions with a high imposed cadence. The steps that immediately preceded these episodes were mainly characterized by an increase in cadence and an increase in stride length variability. The results also underscore that FOG can be elicited in a laboratory setting when patients are placed under considerable strain, at least in advanced stages of PD. Patients were unable to adequately negotiate the extreme imposed cadence condition, and this resulted in frequent FOG episodes, even while walking in an open runway. Placing advanced PD patients into extreme imposed conditions leads to a motor wise and mental collapse response, culminating in FOG. Future work should establish the relevance of these findings for the more common forms of FOG, including brief episodes during turning or gait initiation.
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PMID:Externally provoked freezing of gait in open runways in advanced Parkinson's disease results from motor and mental collapse. 1872 36

Positional asphyxia refers to a situation where there is compromise of respiration because of splinting of the chest and/or diaphragm preventing normal respiratory excursion, or occlusion of the upper airway due to abnormal positioning of the body. Examination of autopsy files at Forensic Science SA revealed instances where positional asphyxia resulted from inadvertent positioning that compromised respiration due to intoxication, multiple sclerosis, epilepsy, Parkinson disease, Steele-Richardson-Olszewski syndrome, Lafora disease and quadriplegia. While the manner of death was accidental in most cases, in one instance suicide could not be ruled out. We would not exclude the possibility of individuals with significant cardiac disease succumbing to positional asphyxia, as cardiac disease may be either unrelated to the terminal episode or, alternatively, may result in collapse predisposing to positional asphyxia. Victims of positional asphyxia do not extricate themselves from dangerous situations due to impairment of cognitive responses and coordination resulting from intoxication, sedation, neurological diseases, loss of consciousness, physical impairment or physical restraints.
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PMID:Conditions and circumstances predisposing to death from positional asphyxia in adults. 1876 6

In Parkinson's disease (PD), there is evidence that alpha-synuclein (alphaSN) aggregation is coupled to dysfunctional or overburdened protein quality control systems, in particular the ubiquitin-proteasome system. Here, we develop a simple dynamical model for the on-going conflict between alphaSN aggregation and the maintenance of a functional proteasome in the healthy cell, based on the premise that proteasomal activity can be titrated out by mature alphaSN fibrils and their protofilament precursors. In the presence of excess proteasomes the cell easily maintains homeostasis. However, when the ratio between the available proteasome and the alphaSN protofilaments is reduced below a threshold level, we predict a collapse of homeostasis and onset of oscillations in the proteasome concentration. Depleted proteasome opens for accumulation of oligomers. Our analysis suggests that the onset of PD is associated with a proteasome population that becomes occupied in periodic degradation of aggregates. This behavior is found to be the general state of a proteasome/chaperone system under pressure, and suggests new interpretations of other diseases where protein aggregation could stress elements of the protein quality control system.
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PMID:Modeling proteasome dynamics in Parkinson's disease. 1941 40

Alpha-synuclein (alphaS) is the primary component of Lewy bodies, the pathological hallmark of Parkinson's Disease. Aggregation of alphaS is thought to proceed from a primarily disordered state with nascent secondary structure through intermediate conformations to oligomeric forms and finally to mature amyloid fibrils. Low pH conditions lead to conformational changes associated with increased alphaS fibril formation. Here we characterize these structural and dynamic changes using solution state NMR measurements of secondary chemical shifts, relaxation parameters, residual dipolar couplings, and paramagnetic relaxation enhancement. We find that the neutralization of negatively charged side-chains eliminates electrostatic repulsion in the C-terminal tail of alphaS and leads to a collapse of this region at low pH. Hydrophobic contacts between the compact C-terminal tail and the NAC (non-amyloid-beta component) region are maintained and may lead to the formation of a globular domain. Transient long-range contacts between the C-terminus of the protein and regions N-terminal to the NAC region are also preserved. Thus, the release of long-range contacts does not play a role in the increased aggregation of alphaS at low pH, which we instead attribute to the increased hydrophobicity of the protein.
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PMID:Charge neutralization and collapse of the C-terminal tail of alpha-synuclein at low pH. 1947 65

Neuromelanin (NM)-containing dopaminergic neurons in the substantia nigra are selectively vulnerable in Parkinson's disease (PD), suggesting the involvement of NM in the pathogenesis. NM is composed of protein, lipid, trace metals and melanin component, a mixture of eumelanin produced from dopamine (DA)-quinone and pheomelanin containing 5-S-cyteinyl-DA-quinone. We reported that NM induces mitochondria-mediated apoptosis in human dopaminergic SH-SY5Y cells, which was suppressed completely by Protease K-treatment, suggesting the essential requirement for the protein component. In this paper, the role of the melanin component in NM-dependent apoptosis was studied using SH-SY5Y cells and synthesized DA-melanin (DAM) and L-cysteinyl-DAM (Cys-DAM). DAM oxidatively decreased glutathione (GSH) and sulfhydryl (SH) content in mitochondria, whereas NM increased GSH by de-S-glutathionylation of complex I. DAM induced mitochondrial permeability transition (mPT), leading to membrane potential collapse and cytochrome c release, whereas Cys-DAM did not. However, the cytotoxicity of DAM itself was rather mild and thiol-targeting reducing reagents, including GSH, dithiothreitol and N-acetyl-cysteine, increased apoptosis significantly. The reducing SH reagents activated caspase 3 and induced apoptosis, but did not affect mPT. On the other hand, NM itself activated mitochondria-initiated apoptotic cascade, which GSH suppressed completely. The results indicate that DAM induces apoptosis through the sequential activation by oxidation of SH status in mitochondria and reduction in cytoplasm, in contrast to the case with NM. The regulation of apoptotic processing by SH redox state is discussed in relation to degeneration of nigra-striatal DA neurons in aging and PD, where oxidative stress is increased with impaired antioxidant capacity.
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PMID:Glutathione redox status in mitochondria and cytoplasm differentially and sequentially activates apoptosis cascade in dopamine-melanin-treated SH-SY5Y cells. 1973

Osteoporotic thoracolumbar compression fracture occasionally occurs in patients with Parkinson's disease and can lead to neural compromise due to delayed vertebral body collapse, requiring surgical treatment. Surgical treatment and postoperative care are difficult because of poor bone quality, involuntary exercise, and postural imbalance. Due to such difficulties in treatment, few reports exist about surgery for osteoporotic thoracolumbar compression fracture in patients with Parkinson's disease. Anterior decompression and posteroanterior reconstructive stabilization were performed for 3 patients with Parkinson's disease and osteoporotic vertebral body collapse. To prevent instrument-related complications, it is important to achieve initial rigid stability. Regarding the stabilization of the posterior elements, laminar hooks were used. Two pedicle screws and 1 hook were placed at 1 level above and 1 level below the injured vertebra. As for the stabilization of the anterior part, a titanium cage was used. All patients resumed their activities of daily living postoperatively. Two of 3 patients experienced sinking of the rib cage after commencement of ambulation with a hard brace postoperatively. After these patients wore a body cast for 2 months, they were able to resume activities of daily living under careful treatment. In all patients, junctional kyphosis improved postoperatively and progressed postoperatively. None experienced recurrent neural deterioration or backache related to the fracture through >3 years of postoperative follow-up. Combined posteroanterior reconstruction surgery was useful for osteoporotic thoracolumbar compression fracture with Parkinson's disease. However, maintenance of postoperative alignment was difficult to achieve. Careful postoperative management was important for good clinical results.
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PMID:Combined posteroanterior surgery for osteoporotic delayed vertebral fracture and neural deficit in patients with Parkinson's disease. 1982

Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARK2/Parkin mutations cause autosomal recessive forms of Parkinson's disease. Upon a loss of mitochondrial membrane potential (DeltaPsi(m)) in human cells, cytosolic Parkin has been reported to be recruited to mitochondria, which is followed by a stimulation of mitochondrial autophagy. Here, we show that the relocation of Parkin to mitochondria induced by a collapse of DeltaPsi(m) relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria, even in cells with normal DeltaPsi(m). We also show that once at the mitochondria, Parkin is in close proximity to PINK1, but we find no evidence that Parkin catalyzes PINK1 ubiquitination or that PINK1 phosphorylates Parkin. However, co-overexpression of Parkin and PINK1 collapses the normal tubular mitochondrial network into mitochondrial aggregates and/or large perinuclear clusters, many of which are surrounded by autophagic vacuoles. Our results suggest that Parkin, together with PINK1, modulates mitochondrial trafficking, especially to the perinuclear region, a subcellular area associated with autophagy. Thus by impairing this process, mutations in either Parkin or PINK1 may alter mitochondrial turnover which, in turn, may cause the accumulation of defective mitochondria and, ultimately, neurodegeneration in Parkinson's disease.
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PMID:PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. 1996 84


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