Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss
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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 and PINK1 and parkin modulation of 4E-BP.
“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]
The Results section ('4E-BP pathway is activated in parkin/PINK1 mutants'; page unavailable) reports altered 4E-BP phosphorylation in PINK1 and parkin mutants and links the pathway to global protein translation. It describes this change as a protective stress response, however, rather than showing that PINK1/parkin modulation of 4E-BP mediates aberrant protein synthesis. The LRRK2 ribosomal-protein clause has separate citations and is not assessed here. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDefects in mRNA translation are linked to autosomal dominant PD and autosomal recessive PD, where there is aberrant bulk protein synthesis coupled to neurodegeneration.
“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]
The Results sections on 4E-BP activity and neuron loss (page unavailable) link altered translation regulation in recessive parkin/PINK1 fly mutants to dopaminergic neurodegeneration: the pathway regulating global translation is down-regulated, and increasing 4E-BP protects neurons. The paper does not establish aberrant bulk protein synthesis itself as coupled to neurodegeneration; it assesses translation-regulatory activity, and describes the existing down-regulation as a protective stress response. (LLM, conf=0.84)
Experimental — accuracy not yet measuredActivation of 4E-BP1 by rapamycin treatment is sufficient to rescue dopamine neuron loss and motor deficits in Drosophila PINK1 and parkin models.
“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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- 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 › 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
- 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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