LRRK2 interactions with α-synuclein in Parkinson's disease brains and in cell models

Patricia Guerreiro, Yue Huang, Amanda Gysbers, Danni Cheng, Wei-Ping Gai, Tiago Outeiro, Glenda Halliday

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    46 Citations (Scopus)

    Abstract

    Mutations in the genes encoding leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are associated with both autosomal dominant and idiopathic forms of Parkinson's disease (PD). α-Synuclein is the main protein in Lewy bodies, hallmark inclusions present in both sporadic and familial PD. We show that in PD brain tissue, the levels of LRRK2 are positively related to the increase in α-synuclein phosphorylation and aggregation in affected brain regions (amygdala and anterior cingulate cortex), but not in the unaffected visual cortex. In disease-affected regions, we show co-localization of these two proteins in neurons and Lewy body inclusions. Further, in vitro experiments show a molecular interaction between α-synuclein and LRRK2 under endogenous and over-expression conditions. In a cell culture model of α-synuclein inclusion formation, LRRK2 co-localizes with the α-synuclein inclusions, and knocking down LRRK2 increases the number of smaller inclusions. In addition to providing strong evidence for an interaction between LRRK2 and α-synuclein, our results shed light on the complex relationship between these two proteins in the brains of patients with PD and the underlying molecular mechanisms of the disease.

    Original languageEnglish
    Pages (from-to)513-522
    Number of pages10
    JournalJOURNAL OF MOLECULAR MEDICINE-JMM
    Volume91
    Issue number4
    DOIs
    Publication statusPublished - Apr 2013

    Keywords

    • α-Synuclein
    • Interaction
    • Lewy bodies
    • LRKK2
    • Parkinson's disease

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    Guerreiro, P., Huang, Y., Gysbers, A., Cheng, D., Gai, W-P., Outeiro, T., & Halliday, G. (2013). LRRK2 interactions with α-synuclein in Parkinson's disease brains and in cell models. JOURNAL OF MOLECULAR MEDICINE-JMM, 91(4), 513-522. https://doi.org/10.1007/s00109-012-0984-y