Tain, L.S., Mortiboys, H., Tao, R.N. et al. (3 more authors) (2009) Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nature Neuroscience , 12 (9). pp. 1129-1135. ISSN 1097-6256
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2009 Nature America, Inc. This is an author produced version of a paper subsequently published in Nature Neuroscience. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Mitochondrial Pathology; Life-Span; Fat-Body; Oxidative Stress; Kinase-Activity; Drosophila; Disease; Translation; Phosphorylation; Pink1 |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 24 Nov 2016 14:24 |
Last Modified: | 26 Mar 2018 16:46 |
Published Version: | https://doi.org/10.1038/nn.2372 |
Status: | Published |
Publisher: | Nature Publishing Group |
Refereed: | Yes |
Identification Number: | 10.1038/nn.2372 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:108027 |