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- Title
LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation.
- Authors
Eun-Jin Bae; Dong-Kyu Kim; Changyoun Kim; Mante, Michael; Adame, Anthony; Rockenstein, Edward; Ulusoy, Ayse; Klinkenberg, Michael; Ga Ram Jeong; Jae Ryul Bae; Cheolsoon Lee; He-Jin Lee; Byung-Dae Lee; Di Monte, Donato A.; Masliah, Eliezer; Seung-Jae Lee
- Abstract
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.
- Publication
Nature Communications, 2018, Vol 9, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-05958-z