TY  - JOUR
AU  - Bae, Eun-Jin
AU  - Kim, Dong-Kyu
AU  - Kim, Changyoun
AU  - Mante, Michael
AU  - Adame, Anthony
AU  - Rockenstein, Edward
AU  - Ulusoy, Ayse
AU  - Klinkenberg, Michael
AU  - Jeong, Ga Ram
AU  - Bae, Jae Ryul
AU  - Lee, Cheolsoon
AU  - Lee, He-Jin
AU  - Lee, Byung-Dae
AU  - Di Monte, Donato A
AU  - Masliah, Eliezer
AU  - Lee, Seung-Jae
TI  - LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation.
JO  - Nature Communications
VL  - 9
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2020-06481
SP  - 3465
PY  - 2018
AB  - 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.
KW  - Animals
KW  - Blotting, Western
KW  - Caenorhabditis elegans: genetics
KW  - Caenorhabditis elegans: metabolism
KW  - Caenorhabditis elegans Proteins: genetics
KW  - Caenorhabditis elegans Proteins: metabolism
KW  - Cell Line, Tumor
KW  - Humans
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
KW  - Microscopy, Fluorescence
KW  - Phosphorylation
KW  - Plasmids: genetics
KW  - Rats
KW  - alpha-Synuclein: genetics
KW  - alpha-Synuclein: metabolism
KW  - rab GTP-Binding Proteins: genetics
KW  - rab GTP-Binding Proteins: metabolism
KW  - Caenorhabditis elegans Proteins (NLM Chemicals)
KW  - Rab-35 protein, C elegans (NLM Chemicals)
KW  - alpha-Synuclein (NLM Chemicals)
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (NLM Chemicals)
KW  - rab GTP-Binding Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30150626
C2  - pmc:PMC6110743
DO  - DOI:10.1038/s41467-018-05958-z
UR  - https://pub.dzne.de/record/140159
ER  -