Abstract
Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is increasingly implicated in various neurodegenerative diseases. Deregulated Cdk5 activity has been associated with neuronal death, but the underlying mechanisms are not well understood. Here we report an unexpected role for Cdk5 in the regulation of induced autophagy in neurons. We have identified endophilin B1 (EndoB1) as a Cdk5 substrate, and show that Cdk5-mediated phosphorylation of EndoB1 is required for autophagy induction in starved neurons. Furthermore, phosphorylation of EndoB1 facilitates EndoB1 dimerization and recruitment of UVRAG (UV radiation resistance-associated gene). More importantly, Cdk5-mediated phosphorylation of EndoB1 is essential for autophagy induction and neuronal loss in models of Parkinson’s disease. Our findings not only establish Cdk5 as a critical regulator of autophagy induction, but also reveal a role for Cdk5 and EndoB1 in the pathophysiology of Parkinson’s disease through modulating autophagy.
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Change history
21 April 2011
In the version of this article initially published online and in print, there were some errors in Fig. 3b. These errors have been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We are grateful to A. B. Kulkarni (National Institutes of Health, USA) and T. Curran (St Jude Children’s Research Hospital, USA) for the Cdk5-knockout mice. p35-knockout mice were provided by L. H. Tsai (Massachusetts Institute of Technology, USA). We thank T. Yoshimori (Osaka University, Japan) for the mRFP–LC3 construct, V. M. Y. Lee (University of Pennsylvania School of Medicine, USA) for the SNL-1 antibody and wild-type α-synuclein and α-synucleinA53T constructs and J. Yuan (Harvard Medical School) for the pcDNA3-Beclin 1 construct. We thank J. Li, G. Ke, W. Y. Fu, K. Cheng, J. Wan, Y. P. Ng, V. Lee and A. Lai for technical assistance, and members of the Ip laboratory for discussions. This work was supported in part by the Research Grants Council of Hong Kong (HKUST 661007, 661109, 660309, 660210, 1/06C and 6/CRF/08), the Area of Excellence Scheme of the University Grants Committee (AoE/B-15/01) and the Hong Kong Jockey Club. N.Y.I. and Z.H.C. were recipients of the Croucher Foundation Senior Research Fellowship and Croucher Foundation Fellowship, respectively.
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A.S.L.W., R.H.K.L., A.Y.C. and P.K.Y. carried out the experiments. A.S.L.W., R.H.K.L., A.Y.C., P.K.Y., Z.H.C. and N.Y.I. planned the studies, designed the experiments and interpreted the results. S.K.C., Z.H.C. and N.Y.I. provided reagents and resources. A.S.L.W., Z.H.C. and N.Y.I. wrote the manuscript. All authors discussed the results and commented on the manuscript.
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Wong, A., Lee, R., Cheung, A. et al. Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease. Nat Cell Biol 13, 568–579 (2011). https://doi.org/10.1038/ncb2217
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DOI: https://doi.org/10.1038/ncb2217
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