@article{5bda1ae073ef4fec929c463999f78598,
title = "LRRK2 phosphorylates novel tau epitopes and promotes tauopathy",
abstract = "Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson's disease (PD). The neuropathology of LRRK2-related PD is heterogeneous and can include aberrant tau phosphorylation or neurofibrillary tau pathology. Recently, LRRK2 has been shown to phosphorylate tau in vitro; however, the major epitopes phosphorylated by LRRK2 and the physiological or pathogenic consequences of these modifications in vivo are unknown. Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/ T205 epitopes. These findings indicate that tau can be a LRRK2 substrate and that this interaction can enhance salient features of human disease.",
author = "Bailey, {Rachel M.} and Covy, {Jason P.} and Melrose, {Heather L.} and Linda Rousseau and Ruth Watkinson and Joshua Knight and Sarah Miles and Farrer, {Matthew J.} and Dickson, {Dennis W.} and Giasson, {Benoit I.} and Jada Lewis",
note = "Funding Information: Acknowledgments We would like to acknowledge support by NINDS (NIH 1F31NS078896-01-A1) to rMB, (r01NS065860) to HlM, (P50NS072187) to DWD, and (5r01NS082672) to Jl and BIg. MJF acknowledges support through the Canada excellence research Chairs program and the Dr. Donald rix BC leadership Chair. This work also was funded by a grant from The ellison Medical Foundation to BIg. Additional support was provided from the Mayo Clinic to HlM, MJF, DWD, and Jl and the University of Florida Department of Neuroscience and Center for Translational research in Neurodegenerative Disease to BIg and Jl. lrrK2 screening was done by MJF and Owen ross at the Mayo Clinic through support from the Udall Center (P50 NS72187). We would like to thank William S. lane and the Harvard Mass Spectrometry and Proteomics resource laboratory (Cambridge, MA) for the mass spectrometry analyses. Clipart for Supplemental Figure 2 was obtained from http://www.biochem.wisc.edu/medialab/clipart.aspx.",
year = "2013",
month = dec,
doi = "10.1007/s00401-013-1188-4",
language = "English (US)",
volume = "126",
pages = "809--827",
journal = "Acta neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "6",
}