LRRK2 activation in idiopathic Parkinson's disease.

Science translational medicine (2018-07-27)
Roberto Di Maio, Eric K Hoffman, Emily M Rocha, Matthew T Keeney, Laurie H Sanders, Briana R De Miranda, Alevtina Zharikov, Amber Van Laar, Antonia F Stepan, Thomas A Lanz, Julia K Kofler, Edward A Burton, Dario R Alessi, Teresa G Hastings, J Timothy Greenamyre
ABSTRACT

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease (PD). However, a potential role of wild-type LRRK2 in idiopathic PD (iPD) remains unclear. Here, we developed proximity ligation assays to assess Ser1292 phosphorylation of LRRK2 and, separately, the dissociation of 14-3-3 proteins from LRRK2. Using these proximity ligation assays, we show that wild-type LRRK2 kinase activity was selectively enhanced in substantia nigra dopamine neurons in postmortem brain tissue from patients with iPD and in two different rat models of the disease. We show that this occurred through an oxidative mechanism, resulting in phosphorylation of the LRRK2 substrate Rab10 and other downstream consequences including abnormalities in mitochondrial protein import and lysosomal function. Our study suggests that, independent of mutations, wild-type LRRK2 plays a role in iPD. LRRK2 kinase inhibitors may therefore be useful for treating patients with iPD who do not carry LRRK2 mutations.

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