Journal Article

DZNE-2020-06481

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation.

Bae, E.-J. ; Kim, D.-K. ; Kim, C. ; Mante, M. ; Adame, A. ; Rockenstein, E. ; Ulusoy, A.DZNE* ; Klinkenberg, M.DZNE* ; Jeong, G. R. ; Bae, J. R. ; Lee, C. ; Lee, H.-J. ; Lee, B.-D. ; Di Monte, D. A.DZNE* ; Masliah, E. ; Lee, S.-J. (Corresponding author)

2018
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-018-05958-z

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.

Keyword(s): Animals (MeSH) ; Blotting, Western (MeSH) ; Caenorhabditis elegans: genetics (MeSH) ; Caenorhabditis elegans: metabolism (MeSH) ; Caenorhabditis elegans Proteins: genetics (MeSH) ; Caenorhabditis elegans Proteins: metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; Humans (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism (MeSH) ; Microscopy, Fluorescence (MeSH) ; Phosphorylation (MeSH) ; Plasmids: genetics (MeSH) ; Rats (MeSH) ; alpha-Synuclein: genetics (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; rab GTP-Binding Proteins: genetics (MeSH) ; rab GTP-Binding Proteins: metabolism (MeSH) ; Caenorhabditis elegans Proteins ; Rab-35 protein, C elegans ; alpha-Synuclein ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; rab GTP-Binding Proteins

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Contributing Institute(s):

1. Neurodegeneration and Neuroprotection in Parkinson´s Disease (AG Di Monte)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2018

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