RTP801 is induced in Parkinson's disease and mediates neuron death by inhibiting Akt phosphorylation/activation.
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.
Malagelada
Cristina
C
Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA. cm2273@columbia.edu
Jin
Zong Hao
ZH
Greene
Lloyd A
LA
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008543:Melanins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D012694:Serine / Q000378:metabolism; D013378:Substantia Nigra / Q000473:pathology; D017783:Superior Cervical Ganglion / Q000166:cytology; D013565:Sympatholytics / Q000494:pharmacology; D013912:Threonine / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection / Q000379:methods
C469991:DDIT4 protein, human; D008543:Melanins; D013565:Sympatholytics; D014157:Transcription Factors; C014121:neuromelanin; D049452:Green Fluorescent Proteins; D013912:Threonine; D012694:Serine; D016627:Oxidopamine; D051058:Oncogene Protein v-akt