@article{45bc259142df475aa2faf51cb713b31c,
title = "Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in parkinson's disease",
abstract = "Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson's disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phosphodeficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phosphodeficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo.",
author = "Ian Martin and Kim, {Jungwoo Wren} and Lee, {Byoung Dae} and Kang, {Ho Chul} and Xu, {Jin Chong} and Hao Jia and Jeannette Stankowski and Kim, {Min Sik} and Jun Zhong and Manoj Kumar and Andrabi, {Shaida A.} and Yulan Xiong and Dickson, {Dennis W.} and Wszolek, {Zbigniew K.} and Akhilesh Pandey and Dawson, {Ted M.} and Dawson, {Valina L.}",
note = "Funding Information: The authors acknowledge the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation and their direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and The Johns Hopkins University School of Medicine and the Foundations{\textquoteright} Parkinson{\textquoteright}s Disease Programs. The authors acknowledge the Johns Hopkins Stem Cell Core Facility for providing a subset of the human neurons used in this study. Funding for a portion of the research described in this article was provided by Merck KGAA. Under a licensing agreement between Merck KGAA and The Johns Hopkins University, Dr. Dawson and the University shared fees received by the University on licensing of some of the reagents described in this article. Dr. Dawson also was a paid consultant to Merck KGAA. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies. Mayo Clinic and Dr. Wszolek have a financial interest in a technology ( LRRK2 gene) referenced in this manuscript. This technology has been licensed to a commercial entity and Mayo Clinic and Dr. Wszolek receive royalties from that license. Dr. Wszolek{\textquoteright}s annual royalties are less than $200 per year. This work was also supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) P50NS038377, the JPB Foundation, and the MDSCRF 2007-MSCRFI-0420-00, 2009-MSCRFII-0125-00, MDSCRF 2013-MSCRFII-0105-00 to T.M.D. and V.L.D., NIH/NINDS P50 NS072187 to D.D. and Z.K.W., and a New York Stem Cell Foundation-Druckenmiller Fellowship to I.M. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. ",
year = "2014",
month = apr,
day = "10",
doi = "10.1016/j.cell.2014.01.064",
language = "English (US)",
volume = "157",
pages = "472--485",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",
}