LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation

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.

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Cited by papers we hold 5

• “LRRK2: Autophagy and Lysosomal Activity” · 2020
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• Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson's disease · 2020
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• Rab family of small GTPases: an updated view on their regulation and functions · 2020
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• G2019s LRRK2 promotes mitochondrial fission and increases TNFα-mediated neuroinflammation responses · 2019
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• LRRK2 modifies α-syn pathology and spread in mouse models and human neurons · 2019
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