Home > Publications Database > LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation. > print

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024 7 _ |a 10.1038/s41467-018-05958-z
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037 _ _ |a DZNE-2020-06481
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Bae, Eun-Jin
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245 _ _ |a LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation.
260 _ _ |a [London]
|c 2018
|b Nature Publishing Group UK
264 _ 1 |3 online
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|b Springer Science and Business Media LLC
|c 2018-08-27
264 _ 1 |3 print
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|b Springer Science and Business Media LLC
|c 2018-12-01
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
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542 _ _ |i 2018-08-27
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650 _ 7 |a Caenorhabditis elegans Proteins
|2 NLM Chemicals
650 _ 7 |a Rab-35 protein, C elegans
|2 NLM Chemicals
650 _ 7 |a alpha-Synuclein
|2 NLM Chemicals
650 _ 7 |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
|0 EC 2.7.11.1
|2 NLM Chemicals
650 _ 7 |a rab GTP-Binding Proteins
|0 EC 3.6.5.2
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Blotting, Western
|2 MeSH
650 _ 2 |a Caenorhabditis elegans: genetics
|2 MeSH
650 _ 2 |a Caenorhabditis elegans: metabolism
|2 MeSH
650 _ 2 |a Caenorhabditis elegans Proteins: genetics
|2 MeSH
650 _ 2 |a Caenorhabditis elegans Proteins: metabolism
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
|2 MeSH
650 _ 2 |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
|2 MeSH
650 _ 2 |a Microscopy, Fluorescence
|2 MeSH
650 _ 2 |a Phosphorylation
|2 MeSH
650 _ 2 |a Plasmids: genetics
|2 MeSH
650 _ 2 |a Rats
|2 MeSH
650 _ 2 |a alpha-Synuclein: genetics
|2 MeSH
650 _ 2 |a alpha-Synuclein: metabolism
|2 MeSH
650 _ 2 |a rab GTP-Binding Proteins: genetics
|2 MeSH
650 _ 2 |a rab GTP-Binding Proteins: metabolism
|2 MeSH
700 1 _ |a Kim, Dong-Kyu
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700 1 _ |a Kim, Changyoun
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700 1 _ |a Mante, Michael
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700 1 _ |a Adame, Anthony
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700 1 _ |a Rockenstein, Edward
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700 1 _ |a Ulusoy, Ayse
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700 1 _ |a Klinkenberg, Michael
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700 1 _ |a Jeong, Ga Ram
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700 1 _ |a Bae, Jae Ryul
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700 1 _ |a Lee, Cheolsoon
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700 1 _ |a Lee, He-Jin
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700 1 _ |a Lee, Byung-Dae
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700 1 _ |a Di Monte, Donato A
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700 1 _ |a Masliah, Eliezer
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700 1 _ |a Lee, Seung-Jae
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773 1 8 |a 10.1038/s41467-018-05958-z
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