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Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss

Nature Neuroscience volume 12, pages 1129–1135 (2009)Cite this article

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.

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Figure 1: 4E-BP overexpression suppresses park and Pink1 locomotor deficits and muscle degeneration.
Figure 2: Overexpression of 4E-BP can suppress degeneration of dopaminergic neurons in park and Pink1 mutants.
Figure 3: Post-translational state of 4E-BP activity in park and Pink1 mutants.
Figure 4: Pharmacological suppression of park and Pink1 mutant phenotypes by rapamycin.
Figure 5: Rapamycin rescues mitochondrial defects in park-deficient Drosophila and PARK2-deficient human cells.
Figure 6: Rapamycin suppression of park and Pink1 phenotypes is dependent on 4E-BP, but does not require autophagy.
Figure 7: GstS1 levels are increased by 4E-BP activation.
Figure 8: Loss of Drosophila LRRK increases the amount hypo-phosphorylated 4E-BP and partially suppresses park and Pink1 mutant phenotypes.

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Acknowledgements

We would like to thank L. Pallanck, P. Ingham and L. Partridge for critical reading of the manuscript and discussions. We would also like to thank J. Chung, S. Birman, L. Partridge, N. Sonenberg and T. Neufeld for Drosophila lines, H. Beneš for the antibody to GstS1 and I. Bjedov for Atg5 qPCR primer sequences. We also acknowledge the Department of Biomedical Science Centre for Electron Microscopy for technical assistance. This work was supported by grants from the Parkinson's Disease Society UK (G-4063 and G-0713 to A.J.W. and G-0715 to O.B.) and the Royal Society and Wellcome Trust (081987) to A.J.W. The MRC Centre for Developmental and Biomedical Genetics is supported by grant G070091. The Wellcome Trust (grant number GR077544AIA) supports the Light Microscopy Facility.

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  1. Luke S Tain

    Present address: Present address: Max Planck Institute for Biology of Ageing, Cologne, Germany.,

Authors and Affiliations

  1. Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, UK

    Luke S Tain, Heather Mortiboys, Ran N Tao, Elena Ziviani, Oliver Bandmann & Alexander J Whitworth

  2. Department of Biomedical Sciences, University of Sheffield, Sheffield, UK

    Luke S Tain, Ran N Tao, Elena Ziviani & Alexander J Whitworth

  3. Academic Neurology Unit, University of Sheffield, Sheffield, UK

    Heather Mortiboys & Oliver Bandmann

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Contributions

L.S.T., H.M., R.N.T., E.Z. and A.J.W. designed and conducted the experiments and analyzed the data. L.S.T. and A.J.W. prepared the figures and wrote the manuscript. A.J.W. and O.B. supervised the project, and contributed to experimental design and data analysis.

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Correspondence to Alexander J Whitworth.

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Tain, L., Mortiboys, H., Tao, R. et al. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat Neurosci 12, 1129–1135 (2009). https://doi.org/10.1038/nn.2372

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