LRRK2 phosphorylates novel tau epitopes and promotes tauopathyReport as inadecuate

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Acta Neuropathologica

, Volume 126, Issue 6, pp 809–827

First Online: 11 October 2013Received: 05 July 2013Accepted: 27 September 2013


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.

Electronic supplementary materialThe online version of this article doi:10.1007-s00401-013-1188-4 contains supplementary material, which is available to authorized users.

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Author: Rachel M. Bailey - Jason P. Covy - Heather L. Melrose - Linda Rousseau - Ruth Watkinson - Joshua Knight - Sarah Miles -


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