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The Journal of Neuroscience, December 31, 2008, 28(53):14363-14371; doi:10.1523/JNEUROSCI.3928-08.2008
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Neurobiology of Disease
RTP801 Is Induced in Parkinson's Disease and Mediates Neuron Death by Inhibiting Akt Phosphorylation/Activation
Cristina Malagelada, Zong Hao Jin, andLloyd A. Greene Department of Pathology and Cell Biology, Columbia University, New York, New York 10032
Correspondence should be addressed to Dr. Cristina Malagelada, Department of Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, Floor 15, Room 401, New York, NY 10032. Email: cm2273{at}columbia.edu
Previously, we reported that RTP801, a stress regulated protein, is induced in multiple cellular models of Parkinson's disease (PD), in an animal model of PD and in dopaminergic neurons of PD patients. In cellular PD models, RTP801 is both sufficient and necessary for death. We further showed that RTP801 and PD mimetics such as 6-OHDA trigger neuron death by suppressing activation of the key kinase mammalian target of rapamycin (mTOR). Here, we report that as a consequence of mTOR signaling blockade, 6-OHDA suppresses the phosphorylation and activation of Akt, a major supporter of neuron survival. This effect is mediated by RTP801 and appears to underlie neuron death induced by 6-OHDA. Examination of postmortem dopaminergic neurons reveals a consistent depletion of phospho-Akt, but not of total Akt in PD patients. These observations support a sequential mechanism in which PD-associated stresses induce RTP801, suppress mTOR signaling, deplete phosphorylated/activated Akt and permit neuron degeneration and death.
Key words: Parkinson's disease; Akt; RTP801; neurodegeneration; 6-hydroxydopamine; mTOR
Received Aug. 15, 2008; revised Oct. 28, 2008; accepted Nov. 5, 2008.
Correspondence should be addressed to Dr. Cristina Malagelada, Department of Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, Floor 15, Room 401, New York, NY 10032. Email: cm2273{at}columbia.edu
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