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RTP801 Is Induced in Parkinson's Disease and Mediates Neuron Death by Inhibiting Akt Phosphorylation/Activation
Open accessAbstract
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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“Previous results indicated that a lower expression of AKT in dopaminergic neurons of PD patients than that in normal people (Malagelada et al. 2008)”
From Therapeutic effect of GLP-1 engineered strain on mice model of Alzheimer’s disease and Parkinson’s disease (2020) · cites this paper as Malagelada et al. 2008
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Metadata
- Authors
- Malagelada, C., Jin, Z. H., & Greene, L. A.
- Affiliations
- Columbia University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-12-31
- Volume
- 28
- Issue
- 53
- Pages
- 14363-14371
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3865436
- 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
- hybrid
- doi.org
- Licence
- 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 › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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