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Bae, Eun-Jin; Kim, Dong-Kyu; Kim, Changyoun; Mante, Michael; Adame, Anthony; Rockenstein, Edward; Ulusoy, Ayse; Klinkenberg, Michael; Jeong, Ga Ram; Bae, Jae Ryul; Lee, Cheolsoon; Lee, He-Jin; Lee, Byung-Dae; Di Monte, Donato A; Masliah, Eliezer; Lee, Seung-Jae
Nature communications, 08/2018, Letnik: 9, Številka: 1Journal Article
Propagation of α-synuclein aggregates has been suggested as a contributing factor in Parkinson's disease (PD) progression. However, the molecular mechanisms underlying α-synuclein aggregation are not fully understood. Here, we demonstrate in cell culture, nematode, and rodent models of PD that leucine-rich repeat kinase 2 (LRRK2), a PD-linked kinase, modulates α-synuclein propagation in a kinase activity-dependent manner. The PD-linked G2019S mutation in LRRK2, which increases kinase activity, enhances propagation efficiency. Furthermore, we show that the role of LRRK2 in α-synuclein propagation is mediated by RAB35 phosphorylation. Constitutive activation of RAB35 overrides the reduced α-synuclein propagation phenotype in lrk-1 mutant C. elegans. Finally, in a mouse model of synucleinopathy, administration of an LRRK2 kinase inhibitor reduced α-synuclein aggregation via enhanced interaction of α-synuclein with the lysosomal degradation pathway. These results suggest that LRRK2-mediated RAB35 phosphorylation is a potential therapeutic target for modifying disease progression.
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