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Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss
Open accessAbstract
Mutations in PINK1 and PARK2 cause autosomal recessive parkinsonism, a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons. To discover potential therapeutic pathways, we identified factors that genetically interact with Drosophila park and Pink1. We found that overexpression of the translation inhibitor Thor (4E-BP) can suppress all of the pathologic phenotypes, including degeneration of dopaminergic neurons in Drosophila. 4E-BP is activated in vivo by the TOR inhibitor rapamycin, which could potently suppress pathology in Pink1 and park mutants. Rapamycin also ameliorated mitochondrial defects in cells from individuals with PARK2 mutations. Recently, 4E-BP was shown to be inhibited by the most common cause of parkinsonism, dominant mutations in LRRK2. We also found that loss of the Drosophila LRRK2 homolog activated 4E-BP and was also able to suppress Pink1 and park pathology. Thus, in conjunction with recent findings, our results suggest that pharmacologic stimulation of 4E-BP activity may represent a viable therapeutic approach for multiple forms of parkinsonism.
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“This aberrant protein synthesis is, in part, mediated by dysregulation of LRRK2 phosphorylation of ribosomal proteins (5,6) and PTEN-induced kinase 1 (PINK1) and parkin modulation of eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP) (7).”
From Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis (2022) · cites this paper as [7]
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“Defects in mRNA translation are linked to autosomal dominant PD (5,6) and autosomal recessive PD (7), where there is aberrant bulk protein synthesis that is coupled to neurodegeneration (8,9).”
From Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis (2022) · cites this paper as [7]
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“Moreover, activation of 4E-BP1 by rapamycin treatment is sufficient to rescue dopamine neuron loss and motor deficits in Drosophila PINK1 and parkin models of DA neuron loss (7).”
From Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis (2022) · cites this paper as [7]
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Cites
1 retracted
FOXO1 Regulates the Expression of 4E-BP1 and Inhibits mTOR Signaling in Mammalian Skeletal Muscle
Southgate, R. J., Neill, B., Prelovsek, O., El‐Osta, A., Kamei, Y., Miura, S., Ezaki, O., McLoughlin, T. J., Zhang, W., Unterman, T. G., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702039200 · Cited by 112
RetractedTOR signaling in growth and metabolism
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787
Levine, B., & Klionsky, D. J. (2004) · Developmental Cell · doi:10.1016/s1534-5807(04)00099-1 · Cited by 3,728
Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans
Murphy, C. T., McCarroll, S. A., Bargmann, C. I., Fraser, A., Kamath, R. S., Ahringer, J., Li, H., & Kenyon, C. (2003) · Nature · doi:10.1038/nature01789 · Cited by 2,280
eIF4 Initiation Factors: Effectors of mRNA Recruitment to Ribosomes and Regulators of Translation
Gingras, A., Raught, B., & Sonenberg, N. (1999) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.68.1.913 · Cited by 2,103
Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin
Clark, I. E., Dodson, M. W., Jiang, C., Cao, J. H., Huh, J. R., Seol, J. H., Yoo, S. J., Hay, B. A., & Guo, M. (2006) · Nature · doi:10.1038/nature04779 · Cited by 1,788
Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin
Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S., Bae, E., Kim, J., Shong, M., Kim, J.-M., et al. (2006) · Nature · doi:10.1038/nature04788 · Cited by 1,705
Regulation of translation initiation by FRAP/mTOR
Gingras, A.-C., Raught, B., & Sonenberg, N. (2001) · Genes & Development · doi:10.1101/gad.887201 · Cited by 1,545
Translational control in stress and apoptosis
Holčı́k, M., & Sonenberg, N. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1618 · Cited by 1,409
Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway
Kapahi, P., Zid, B. M., Harper, T., Koslover, D., Sapin, V., & Benzer, S. (2004) · Current Biology · doi:10.1016/j.cub.2004.03.059 · Cited by 1,293
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Pathogenic Lysosomal Depletion in Parkinson's Disease
Dehay, B., Bové, J., Rodríguez-Muela, N., Perier, C., Recasens, A., Boya, P., & Vila, M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1920-10.2010 · Cited by 825
Metadata
- Authors
- Tain, L. S., Mortiboys, H., Tao, R. N., Ziviani, E., Bandmann, O., & Whitworth, A. J.
- Affiliations
- Medical Research Council (GB)
- Corresponding author
- Whitworth, Alexander J
- Venue
- Nature Neuroscience
- Published
- 2009-08-16
- Volume
- 12
- Issue
- 9
- Pages
- 1129-1135
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2745154
- OpenAlex
- W1991190713
- Cited by
- 323
- References
- 50
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 11 · 2023: 9 · 2022: 11 · 2021: 9 · 2020: 18 · 2019: 17 · 2018: 14 · 2017: 17 · 2016: 26 · 2015: 21 · 2014: 24 · 2013: 18 · 2012: 27
- FWCI
- 24.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- Wellcome Trust (081987, GR077544AIA)
- Parkinson's UK (G-0713, G-1007, G-4063, G-0715)
- 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
- 4E-BP, rapamycin, Parkinson's disease, Parkin, PINK1, dopaminergic neuron loss, protein synthesis inhibition, TOR signaling, LRRK2, mitochondrial defects, genetic interactions, Drosophila, neurodegeneration, therapeutic target
- MeSH terms
- PTEN-Induced Putative Kinase, Animals, Cell Survival, Dopamine, Drosophila, Fibroblasts, Glutathione Transferase, Humans, Locomotion, Mitochondria, Muscles, Nerve Degeneration, Neurons, Peptide Initiation Factors, Protein Serine-Threonine Kinases, Neuroprotective Agents, Sirolimus, Drosophila Proteins, Animals, Genetically Modified, Ubiquitin-Protein Ligases, Intracellular Signaling Peptides and Proteins
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