RRC ID 55859
Author Bae EJ, Kim DK, Kim C, Mante M, Adame A, Rockenstein E, Ulusoy A, Klinkenberg M, Jeong GR, Bae JR, Lee C, Lee HJ, Lee BD, Di Monte DA, Masliah E, Lee SJ.
Title LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation.
Journal Nat Commun
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.
Volume 9(1)
Pages 3465
Published 2018-8-27
DOI 10.1038/s41467-018-05958-z
PII 10.1038/s41467-018-05958-z
PMID 30150626
PMC PMC6110743
MeSH Animals Blotting, Western Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Line, Tumor Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism* Microscopy, Fluorescence Phosphorylation Plasmids / genetics* Rats alpha-Synuclein / genetics alpha-Synuclein / metabolism* rab GTP-Binding Proteins / genetics rab GTP-Binding Proteins / metabolism*
IF 11.878
Times Cited 36
C.elegans tm1898 tm2058