Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
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Target Concepts:
Gene/Protein
Disease
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Enzyme
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Query: EC:2.7.11.10 (
IKK
)
4,900
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in substantia nigra with unknown etiology. Neuropathology seen in the brains of PD patients can be closely mimicked by
MPP
(+)-induced neurotoxicity in vitro. In this study, we used an S-type human neuroblastoma cell line (SH-EP1) as a model to investigate the involvement of NF-kappaB and JNK pathways in
MPP
(+)-induced neurotoxicity. We show that NF-kappaB was activated by
MPP
(+) as evidenced by NF-kappaB p65 nuclear translocation, the increased DNA binding activity and a rapid phosphorylation of NF-kappaB inhibitor (IkappaBalpha). NF-kappaB partially mediated the neurotoxicity of
MPP
(+), as suggested by the reduction of
MPP
(+)-induced cell death by both a specific
IkappaB kinase
(
IKK
) inhibitor and a dominant negative form of IkappaBalpha (IkappaBalpha-M). Besides NF-kappaB, JNK and c-Jun/AP-1 were also activated upon
MPP
(+) stimulation. Inhibition of JNK activation with a specific JNK inhibitor partially reduced the
MPP
(+)-mediated cell death. Similarly, inhibition of c-Jun/AP-1 activation, either by a dominant negative c-Jun or c-Jun/AP-1 inhibitor, significantly attenuated
MPP
(+)-mediated cell death. These results suggest that both JNK and c-Jun/AP-1 activation are pro-apoptotic. Furthermore, we provide clear evidence for the existence of a crosstalk between the NF-kappaB and JNK signaling as
MPP
(+)-induced activation of JNK and c-Jun/AP-1 was strongly down-regulated in IkappaBalpha-M cells. In conclusion, we demonstrate that in SH-EP1 cells
MPP
(+)-induced neurotoxicity is partially mediated by NF-kappaB which in turn acts on the activation of JNK and c-Jun/AP-1. These results may point to a combined inhibition of NF-kappaB and JNK as a new approach to PD therapy.
...
PMID:NF-kappaB mediates MPP+-induced apoptotic cell death in neuroblastoma cells SH-EP1 through JNK and c-Jun/AP-1. 1977 65
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
