@article{a85bfb49d4434acf9b9a1f985964b161,
title = "Impairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson's disease",
abstract = "The etiology of idiopathic Parkinson's disease (idPD) remains enigmatic despite recent successes in identification of genes (PARKs) that underlie familial PD. To find new keys to this incurable neurodegenerative disorder we focused on the poorly understood PARK14 disease locus (Pla2g6 gene) and the store-operated Ca2+ signalling pathway. Analysis of the cells from idPD patients reveals a significant deficiency in store-operated PLA2g6-dependent Ca2+ signalling, which we can mimic in a novel B6.Cg-Pla2g6ΔEx2-VB (PLA2g6 ex2KO) mouse model. Here we demonstrate that genetic or molecular impairment of PLA2g6-dependent Ca2+ signalling is a trigger for autophagic dysfunction, progressive loss of dopaminergic (DA) neurons in substantia nigra pars compacta and age-dependent L-DOPA-sensitive motor dysfunction. Discovery of this previously unknown sequence of pathological events, its association with idPD and our ability to mimic this pathology in a novel genetic mouse model opens new opportunities for finding a cure for this devastating neurodegenerative disease.",
author = "Qingde Zhou and Allen Yen and Grzegorz Rymarczyk and Hirohide Asai and Chelsea Trengrove and Nadine Aziz and Kirber, {Michael T.} and Gustavo Mostoslavsky and Tsuneya Ikezu and Benjamin Wolozin and Bolotina, {Victoria M.}",
note = "Funding Information: This study is dedicated to Mr Mark D. Bolotin, one of the victims of idPD. We are grateful to Dr G. Krapivinsky and Dr R. Cohen for valuable discussions, expert comments and edits to the manuscript. Special thanks to Dr R. Myers, Dr L. Goldstein and Dr P. Csutora for valuable discussions. We are thankful to S. Zaitsev, J. Meltzer, K. Ingraham, M.S. Khan, Y. Yao, M. Wojnarowicz and M. Segawa for technical assistance at different stages of this project, to G. Ngoh for help with primary MEF cells isolation, to Dr D.L. Rosene for expert guidance and help with stereological analysis and to Dr A. Sommer for help with iPSC. We acknowledge NINDS Cell Line Repository (http://ccr.coriell.org/ninds) for providing the samples of human skin fibroblasts. We also acknowledge help from the Center of Interdisciplinary Research, the Center for Regenerative Medicine (CReM), Cellular Imaging Core, and Instrumentation Core of the Department of Medicine at the Boston University School of Medicine. We are grateful for PLA2g6(L) cDNA provided by MERCK FROSST Canada Ltd and for Orai1KO mice provided by Dr M. Vig. This work was partially supported by Research grant awards from the Michael J. FOX foundation, the US National Institutes of Health (RO1HL71793), Institut de Recherche Servier and the Department of Medicine at Boston University School of Medicine.",
year = "2016",
month = jan,
day = "12",
doi = "10.1038/ncomms10332",
language = "English (US)",
volume = "7",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}