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000140159 1001_ $$0P:(DE-HGF)0$$aBae, Eun-Jin$$b0
000140159 245__ $$aLRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation.
000140159 260__ $$a[London]$$bNature Publishing Group UK$$c2018
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000140159 520__ $$aPropagation 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.
000140159 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000140159 542__ $$2Crossref$$i2018-08-27$$uhttps://creativecommons.org/licenses/by/4.0
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000140159 650_7 $$2NLM Chemicals$$aCaenorhabditis elegans Proteins
000140159 650_7 $$2NLM Chemicals$$aRab-35 protein, C elegans
000140159 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000140159 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
000140159 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$arab GTP-Binding Proteins
000140159 650_2 $$2MeSH$$aAnimals
000140159 650_2 $$2MeSH$$aBlotting, Western
000140159 650_2 $$2MeSH$$aCaenorhabditis elegans: genetics
000140159 650_2 $$2MeSH$$aCaenorhabditis elegans: metabolism
000140159 650_2 $$2MeSH$$aCaenorhabditis elegans Proteins: genetics
000140159 650_2 $$2MeSH$$aCaenorhabditis elegans Proteins: metabolism
000140159 650_2 $$2MeSH$$aCell Line, Tumor
000140159 650_2 $$2MeSH$$aHumans
000140159 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
000140159 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
000140159 650_2 $$2MeSH$$aMicroscopy, Fluorescence
000140159 650_2 $$2MeSH$$aPhosphorylation
000140159 650_2 $$2MeSH$$aPlasmids: genetics
000140159 650_2 $$2MeSH$$aRats
000140159 650_2 $$2MeSH$$aalpha-Synuclein: genetics
000140159 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000140159 650_2 $$2MeSH$$arab GTP-Binding Proteins: genetics
000140159 650_2 $$2MeSH$$arab GTP-Binding Proteins: metabolism
000140159 7001_ $$0P:(DE-HGF)0$$aKim, Dong-Kyu$$b1
000140159 7001_ $$0P:(DE-HGF)0$$aKim, Changyoun$$b2
000140159 7001_ $$0P:(DE-HGF)0$$aMante, Michael$$b3
000140159 7001_ $$0P:(DE-HGF)0$$aAdame, Anthony$$b4
000140159 7001_ $$0P:(DE-HGF)0$$aRockenstein, Edward$$b5
000140159 7001_ $$0P:(DE-2719)2772760$$aUlusoy, Ayse$$b6$$udzne
000140159 7001_ $$0P:(DE-2719)2810845$$aKlinkenberg, Michael$$b7$$udzne
000140159 7001_ $$0P:(DE-HGF)0$$aJeong, Ga Ram$$b8
000140159 7001_ $$0P:(DE-HGF)0$$aBae, Jae Ryul$$b9
000140159 7001_ $$0P:(DE-HGF)0$$aLee, Cheolsoon$$b10
000140159 7001_ $$0P:(DE-HGF)0$$aLee, He-Jin$$b11
000140159 7001_ $$0P:(DE-HGF)0$$aLee, Byung-Dae$$b12
000140159 7001_ $$0P:(DE-2719)2481741$$aDi Monte, Donato A$$b13$$udzne
000140159 7001_ $$0P:(DE-HGF)0$$aMasliah, Eliezer$$b14
000140159 7001_ $$0P:(DE-HGF)0$$aLee, Seung-Jae$$b15$$eCorresponding author
000140159 77318 $$2Crossref$$3journal-article$$a10.1038/s41467-018-05958-z$$b : Springer Science and Business Media LLC, 2018-08-27$$n1$$p3465$$tNature Communications$$v9$$x2041-1723$$y2018
000140159 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-018-05958-z$$gVol. 9, no. 1, p. 3465$$n1$$p3465$$q9:1<3465$$tNature Communications$$v9$$x2041-1723$$y2018
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