Cited by 228Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingAutophagy in Disease and Therapy

RTP801 Is Induced in Parkinson's Disease and Mediates Neuron Death by Inhibiting Akt Phosphorylation/Activation

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Malagelada, Cristina, Jin, Zong Hao, Greene, Lloyd A.·2008·The Journal of Neuroscience

Abstract

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.

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Authors
Malagelada, C., Jin, Z. H., & Greene, L. A.
Affiliations
Columbia University (US)
Venue
The Journal of Neuroscience
Published
2008-12-31
Volume
28
Issue
53
Pages
14363-14371
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2084140068
Cited by
228
References
50
Citations by year
2026: 8 · 2025: 9 · 2024: 8 · 2023: 10 · 2022: 15 · 2021: 20 · 2020: 13 · 2019: 17 · 2018: 10 · 2017: 9 · 2016: 19 · 2015: 11 · 2014: 15 · 2013: 13 · 2012: 19
FWCI
6.80
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Parkinson's Disease Foundation
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (P50NS038370)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
RTP801, Parkinson's disease, dopaminergic neuron death, Akt phosphorylation, mTOR signaling, 6-hydroxydopamine, neurodegeneration, stress response, Akt/mTOR signaling
MeSH terms
Analysis of Variance, Animals, Animals, Newborn, Cells, Cultured, Gene Expression Regulation, Humans, Melanins, Neurons, Parkinson Disease, Phosphorylation, Serine, Substantia Nigra, Sympatholytics, Threonine, Time Factors, Transcription Factors, Transfection, Oxidopamine, Cell Death, Superior Cervical Ganglion, Green Fluorescent Proteins, Oncogene Protein v-akt, Rats

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