Abstract
We report that rapamycin, an allosteric inhibitor of certain but not all actions of the key cellular kinase mammalian target of rapamycin (mTOR), protects neurons from death in both cellular and animal toxin models of Parkinson's disease (PD). This protective action appears to be attributable to blocked translation of RTP801/REDD1/Ddit4, a protein that is induced in cell and animal models of PD and in affected neurons of PD patients and that causes neuron death by leading to dephosphorylation of the survival kinase Akt. In support of this mechanism, in PD models, rapamycin spares phosphorylation of Akt at a site critical for maintenance of its survival-promoting activity. The capacity of rapamycin to provide neuroprotection in PD models appears to arise from its selective suppression of some but not all actions of mTOR, as indicated by the contrasting finding that Torin1, a full catalytic mTOR inhibitor, is not protective and induces Akt dephosphorylation and neuron death.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
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Analysis of Variance
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Animals
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Cell Death / drug effects
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Cycloheximide / pharmacology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Administration Schedule
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / drug effects
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Green Fluorescent Proteins / genetics
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Nerve Growth Factor / pharmacology
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Neurons / drug effects*
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Neuroprotective Agents / therapeutic use*
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Oxidopamine / toxicity
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PC12 Cells
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Parkinson Disease
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Parkinsonian Disorders / chemically induced
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Parkinsonian Disorders / pathology*
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Parkinsonian Disorders / prevention & control*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Rats
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Serine / metabolism
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Sirolimus / therapeutic use*
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TOR Serine-Threonine Kinases
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Time Factors
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / pharmacology
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Transfection / methods
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Tyrosine 3-Monooxygenase / metabolism
Substances
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DDIT4 protein, human
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Neuroprotective Agents
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Transcription Factors
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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Serine
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Oxidopamine
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Nerve Growth Factor
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Cycloheximide
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Tyrosine 3-Monooxygenase
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MTOR protein, human
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mTOR protein, mouse
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Sirolimus