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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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.