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Structural basis for Parkinson's disease-linked LRRK2's binding to microtubules.

ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) is one of the most commonly mutated genes in familial Parkinson's disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an association enhanced by PD mutations. We report a cryo-EM structure of the catalytic half of LRRK2, containing its kinase, in a closed conformation, and GTPase domains, bound to microtubules. We also report a structure of the catalytic half of LRRK1, which is closely related to LRRK2 but is not linked to PD. Although LRRK1's structure is similar to that of LRRK2, we find that LRRK1 does not interact with microtubules. Guided by these structures, we identify amino acids in LRRK2's GTPase that mediate microtubule binding; mutating them disrupts microtubule binding in vitro and in cells, without affecting LRRK2's kinase activity. Our results have implications for the design of therapeutic LRRK2 kinase inhibitors.

SUBMITTER: Snead DM

PROVIDER: S-EPMC9758056 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Structural basis for Parkinson's disease-linked LRRK2's binding to microtubules.

Snead David M DM Matyszewski Mariusz M Dickey Andrea M AM Lin Yu Xuan YX Leschziner Andres E AE Reck-Peterson Samara L SL

Nature structural & molecular biology 20221212 12

Leucine-rich repeat kinase 2 (LRRK2) is one of the most commonly mutated genes in familial Parkinson's disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an association enhanced by PD mutations. We report a cryo-EM structure of the catalytic half of LRRK2, containing its kinase, in a closed conformation, and GTPase domains, bound to microtubules. We also report a structure of the catalytic half of LRRK1, which is closely related to LRRK2 but is not linked to P ...[more]

PMID: 36510024

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Antioxidants inhibit neuronal toxicity in Parkinson's disease-linked LRRK2.

Project description:Mutations in leucine-rich repeat kinase-2 are the most common cause of familial Parkinson's disease. The prevalent G2019S mutation increase oxidative, kinase and toxic activity and inhibit endogenous peroxidases. We initially screened a library of 84 antioxidants and identified seven phenolic compounds that inhibited kinase activity on leucine-rich repeat kinase-2 substrates. The representative antioxidants (piceatannol, thymoquinone, and esculetin) with strong kinase inhibitor activity, reduced loss in dopaminergic neurons, oxidative dysfunction, and locomotor defects in G2019S-expressing neuronal and Drosophila models compared to weak inhibitors. We provide proof of principle that natural antioxidants with dual antioxidant and kinase inhibitor properties could be useful for leucine-rich repeat kinase-2-linked Parkinson's disease.

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Project description:This SuperSeries is composed of the SubSeries listed below.

2015-12-01 | GSE51923 | GEO

Structural Biology of LRRK2 and its Interaction with Microtubules.

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Project description:Idiopathic and LRRK2-associated Parkinson's disease

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