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Pivot Concepts:
Gene/Protein
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Target Concepts:
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Query: EC:4.1.99.3 (
PRE
)
1,923
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
MPP
(+) (1-methyl-4-phenylpyridinium; the active metabolite of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine)) depletes dopamine (DA) content and elicits cell death in PC12 cells. However, the mechanism of
MPP
(+)-induced neurotoxicity is still unclear. In this study, the dose response and time-course of
MPP
(+)-induced DA depletion and decreased cell viability were determined in nerve growth factor (NGF)-differentiated PC12 cells. The alteration of transcription factors (TFs) induced by
MPP
(+) from a selected dose level and time point was then evaluated using protein/DNA-binding arrays. K-means clustering analysis identified four patterns of protein/DNA-binding changes. Three of the 28 TFs identified in PC12 cells increased by 100% (p53,
PRE
, Smad SBE) and 2 decreased by 50% (HSE, RXR(DR1)) of control with
MPP
(+) treatment. In addition, three TFs decreased within the range of 33-50% (TFIID, E2F1, CREB) and two TFs increased within the range of 50-100% (PAX-5, Stat4). An electrophoretic mobility shift assay (EMSA) was used to confirm the changes of p53 and HSE. The observed changes in TFs correlated with the alterations of DA and cell viability. The data indicates that selective transcription factors are involved in
MPP
(+)-induced neurotoxicity and it provides mechanistic information that may be applicable to animal studies with MPTP and clinical studies of Parkinson's disease.
...
PMID:Selective alterations of transcription factors in MPP+-induced neurotoxicity in PC12 cells. 1611 30
Mitochondria are essential for neuronal survival and function, and mitochondrial dysfunction plays a critical role in the pathological development of Parkinson's disease (PD). Mitochondrial quality control is known to contribute to the survival of dopaminergic (DA) neurons, with mitophagy being a key regulator of the quality control system. In this study, we show that mitophagy is impaired in the substantia nigrapars compacta (SNc) of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Treatment with the sigma-1 receptor (Sig 1R) agonist 2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate (
PRE
-084) reduced loss of DA neurons, restored motor ability andMPTP-induced damage to mitophagy activity in the SNc of PD-like mice. Additionally, knockdown of Sig 1R in SH-SY5Y DA cells inhibited mitophagy and enhanced 1-methyl-4-phenylpyridinium ion (
MPP
+
) neurotoxicity, whereas application of the Sig 1R selective agonist SKF10047 promoted clearance of damaged mitochondria. Moreover, knockdown of Sig 1R in SH-SY5Y cells resulted in decreased levels of p-ULK1 (Unc-51 Like Autophagy Activating Kinase 1) (Ser
555
), p-TBK1 (TANK Binding Kinase 1) (Ser
172
), p-ubiquitin (Ub) (Ser
65
), Parkin recruitment, and stabilization of PTEN-induced putative kinase 1 (PINK1) in mitochondria. The present data provide the first evidence for potential roles of PINK1/Parkin in Sig 1R-modulated mitophagy in DA neurons.
...
PMID:Sigma-1 receptor regulates mitophagy in dopaminergic neurons and contributes to dopaminergic protection. 3312 30
