@article{685eb7fd118645f69b31e175387e23ab,
title = "Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function",
abstract = "The role of the serine protease HtrA2 in neuroprotection was initially identified by the demonstration of neurodegeneration in mice lacking HtrA2 expression or function, and the interesting finding that mutations adjacent to two putative phosphorylation sites (S142 and S400) have been found in Parkinson's disease patients. However, the mechanism of this neuroprotection and the signalling pathways associated with it remain mostly unknown. Here we report that cyclin-dependent kinase-5 (Cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating HtrA2 at S400. HtrA2 and Cdk5 interact in human and mouse cell lines and brain, and Cdk5 phosphorylates S400 on HtrA2 in a p38-dependent manner. Phosphorylation of HtrA2 at S400 is involved in maintaining mitochondrial membrane potential under stress conditions and is important for mitochondrial function, conferring cells protection against cellular stress.",
keywords = "Cdk5, HtrA2, Parkinson's disease, mitochondria, phosphorylation",
author = "Fitzgerald, {J. C.} and Camprubi, {M. D.} and L. Dunn and Wu, {H. C.} and Ip, {N. Y.} and R. Kruger and Martins, {L. M.} and Wood, {N. W.} and H. Plun-Favreau",
note = "Funding Information: Acknowledgements. We thank Dr. Mina Ryten (UCL, Institute of Neurology) and the MRC Sudden Death Brain Bank, Edinburgh, for providing the control human brain tissue for co-IP experiments; Dr. Florian Plattner (UCL, Institute of Neurology) for providing the p25-overexpressing mouse brains and the WT age-matched controls; Dr. Emma Deas (UCL, Institute of Neurology) for providing the SH-SY5Y cells stably expressing dsREDmito. This work was supported by a career development award from the MRC (G0700183). This work was also supported in part by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson{\textquoteright}s Disease Consortium (UKPDC) whose members are from the UCL/Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee. The generation and characterisation of HtrA2 transgenic mice were supported by grants from the Faculty of Medicine, University of T{\"u}bingen (Fortuene 1517-0-0) and the German Research Council (DFG, KR2119/3-2) to RK.",
year = "2012",
month = feb,
doi = "10.1038/cdd.2011.90",
language = "English",
volume = "19",
pages = "257--266",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Springer Nature",
number = "2",
}