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The Journal of Neuroscience, January 16, 2008, 28(3):672-680; doi:10.1523/JNEUROSCI.2132-07.2008

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Neurobiology of Disease
Antiapoptotic and Trophic Effects of Dominant-Negative Forms of Dual Leucine Zipper Kinase in Dopamine Neurons of the Substantia Nigra In Vivo

Xiqun Chen,¹ Margarita Rzhetskaya,¹ Tatyana Kareva,¹ Ross Bland,³ Matthew J. During,⁴ A. William Tank,⁵ Nikolai Kholodilov,¹ and Robert E. Burke^1,2

Departments of ¹Neurology and ²Pathology, The College of Physicians and Surgeons, Columbia University, New York, New York 10032, ³Neurologix Research, Fort Lee, New Jersey 07024, ⁴The Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, and ⁵Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642

Correspondence should be addressed to Robert E. Burke, Department of Neurology, Room 306, Black Building, Columbia University, 650 West 168th Street, New York, NY 10032. Email: rb43{at}columbia.edu

There is extensive evidence that the mitogen-activated protein kinase (MAPK) signaling cascade mediates programmed cell death in neurons. However, current evidence that the mixed linage kinases (MLKs), upstream in this cascade, mediate cell death is based, in the in vivo context, entirely on pharmacological approaches. The compounds used in these studies have neither complete specificity nor selectivity among these kinases. Therefore, to better address the molecular specificity of the MLKs in mediating neuron death, we used dominant-negative constructs delivered by AAV (adenoassociated virus) vector transfer. We assessed effects in a neurotoxin model of parkinsonism, in which neuroprotection by pharmacologic MLK inhibition has been reported. We find that two dominant-negative forms of dual leucine zipper kinase (DLK) inhibit apoptosis and enhance long-term survival of dopamine neurons, but a dominant negative of MLK3 does not. Interestingly, the kinase-dead form of DLK not only blocks apoptosis but also has trophic effects on dopamine neurons. Although the MAPK cascade activates a number of downstream cell death mediators, we find that inhibition of DLK correlates closely with blockade of phosphorylation of c-jun and prevention of cell death. We conclude that DLK acts primarily through c-jun phosphorylation to mediate cell death in this model.

Key words: apoptosis; programmed cell death; Parkinson's disease; substantia nigra; mixed lineage kinases; dopamine

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Received May 9, 2007; revised Oct. 29, 2007; accepted Nov. 25, 2007.

Correspondence should be addressed to Robert E. Burke, Department of Neurology, Room 306, Black Building, Columbia University, 650 West 168th Street, New York, NY 10032. Email: rb43{at}columbia.edu

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