%0 Journal Article
%A Bae, Eun-Jin
%A Kim, Dong-Kyu
%A Kim, Changyoun
%A Mante, Michael
%A Adame, Anthony
%A Rockenstein, Edward
%A Ulusoy, Ayse
%A Klinkenberg, Michael
%A Jeong, Ga Ram
%A Bae, Jae Ryul
%A Lee, Cheolsoon
%A Lee, He-Jin
%A Lee, Byung-Dae
%A Di Monte, Donato A
%A Masliah, Eliezer
%A Lee, Seung-Jae
%T LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation.
%J Nature Communications
%V 9
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M DZNE-2020-06481
%P 3465
%D 2018
%X 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.
%K Animals
%K Blotting, Western
%K Caenorhabditis elegans: genetics
%K Caenorhabditis elegans: metabolism
%K Caenorhabditis elegans Proteins: genetics
%K Caenorhabditis elegans Proteins: metabolism
%K Cell Line, Tumor
%K Humans
%K Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
%K Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
%K Microscopy, Fluorescence
%K Phosphorylation
%K Plasmids: genetics
%K Rats
%K alpha-Synuclein: genetics
%K alpha-Synuclein: metabolism
%K rab GTP-Binding Proteins: genetics
%K rab GTP-Binding Proteins: metabolism
%K Caenorhabditis elegans Proteins (NLM Chemicals)
%K Rab-35 protein, C elegans (NLM Chemicals)
%K alpha-Synuclein (NLM Chemicals)
%K Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (NLM Chemicals)
%K rab GTP-Binding Proteins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30150626
%2 pmc:PMC6110743
%R 10.1038/s41467-018-05958-z
%U https://pub.dzne.de/record/140159