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Sci Transl Med. 2018 Jul 25;10(451). pii: eaar5429. doi: 10.1126/scitranslmed.aar5429.

LRRK2 activation in idiopathic Parkinson's disease.

Author information

1
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA.
2
Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
3
Ri.MED Foundation, Palermo, Italy.
4
Department of Neurology, Duke University, Durham, NC 27710, USA.
5
Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, USA.
6
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
7
Geriatric Research, Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
8
MRC Protein Phosphorylation and Ubiquitylation Units, University of Dundee, Dundee, Scotland.
9
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. jgreena@pitt.edu.

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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