Journal article
Inhibition of mixed lineage kinase 3 attenuates MPP +-induced neurotoxicity in SH-SY5Y cells
Brain research, v 1003(1), pp 86-97
02 Apr 2004
PMID: 15019567
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The neuropathology of Parkinson's Disease has been modeled in experimental animals following MPTP treatment and in dopaminergic cells in culture treated with the MPTP neurotoxic metabolite, MPP
+. MPTP through MPP
+ activates the stress-activated c-Jun N-terminal kinase (JNK) pathway in mice and SH-SY5Y neuroblastoma cells. Recently, it was demonstrated that CEP-1347/KT7515 attenuated MPTP-induced nigrostriatal dopaminergic neuron degeneration in mice, as well as MPTP-induced JNK phosphorylation. Presumably, CEP-1347 acts through inhibition of at least one upstream kinase within the mixed lineage kinase (MLK) family since it has been shown to inhibit MLK 1, 2 and 3 in vitro. Activation of the MLK family leads to JNK activation. In this study, the potential role of MLK and the JNK pathway was examined in MPP
+-induced cell death of differentiated SH-SY5Y cells using CEP-1347 as a pharmacological probe and dominant negative adenoviral constructs to MLKs. CEP-1347 inhibited MPP
+-induced cell death and the morphological features of apoptosis. CEP-1347 also prevented MPP
+-induced JNK activation in SH-SY5Y cells. Endogenous MLK 3 expression was demonstrated in SH-SY5Y cells through protein levels and RT-PCR. Adenoviral infection of SH-SY5Y cells with a dominant negative MLK 3 construct attenuated the MPP
+-mediated increase in activated JNK levels and inhibited neuronal death following MPP
+ addition compared to cultures infected with a control construct. Adenoviral dominant negative constructs of two other MLK family members (MLK 2 and DLK) did not protect against MPP
+-induced cell death. These studies show that inhibition of the MLK 3/JNK pathway attenuates MPP
+-mediated SH-SY5Y cell death in culture and supports the mechanism of action of CEP-1347 as an MLK family inhibitor.
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Details
- Title
- Inhibition of mixed lineage kinase 3 attenuates MPP +-induced neurotoxicity in SH-SY5Y cells
- Creators
- Joanne R. Mathiasen - Neurobiology, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USABeth Ann W. McKenna - Neurobiology, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USAMichael S. Saporito - Neurobiology, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USAGhanashyam D. Ghadge - University of ChicagoRaymond P. Roos - University of ChicagoBeverly P. Holskin - Neurobiology, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USAZhi-Liang Wu - Neurobiology, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USAStephen P. Trusko - Neurobiology, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USAThomas C. Connors - Neurobiology, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USAAnna C. Maroney - Neurobiology, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USABeth Ann Thomas - Neurobiology, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USAJeffrey C. Thomas - Neurobiology, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USADonna Bozyczko-Coyne - Neurobiology, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA
- Publication Details
- Brain research, v 1003(1), pp 86-97
- Publisher
- Elsevier
- Number of pages
- 12
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000220830000011
- Scopus ID
- 2-s2.0-12144290127
- Other Identifier
- 991021900191804721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Neurosciences