Research ArticleParkinson’s Disease

LRRK2 activation in idiopathic Parkinson’s disease

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Science Translational Medicine  25 Jul 2018:
Vol. 10, Issue 451, eaar5429
DOI: 10.1126/scitranslmed.aar5429

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Proximity matters

Abnormally increased kinase activity due to mutations in the leucine-rich repeat kinase 2 (LRRK2) gene is the cause of Parkinson’s disease (PD) in about 3 to 4% of patients with this neurodegenerative disorder. Di Maio and colleagues now show that in postmortem brain tissue from individuals with idiopathic PD (iPD), LRRK2 kinase activity is aberrantly increased in vulnerable nigrostriatal dopamine neurons. The authors propose that oxidative stress involving α-synuclein and mitochondrial impairment activated LRRK2 kinase activity and that this caused endolysosomal dysfunction and accumulation of phosphorylated α-synuclein in the brains of these individuals. Thus, activation of LRRK2 kinase activity, independent of mutations, contributes to pathogenesis in iPD, suggesting that LRRK2 kinase inhibitors may be useful for treating patients with iPD and PD patients carrying LRRK2 mutations.

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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