LRRK2 recruitment, activity, and function in organelles

Bonet-Ponce, Luis; Cookson, Mark

doi:10.1111/febs.16099

Cited by 54 publications

(45 citation statements)

References 162 publications

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“…While it remains unclear how LRRK2 drives PD, LRRK2 has been functionally linked to membrane trafficking [12][13][14] . Mutant LRRK2 causes defects in endo/lysosomal, autophagosomal, and mitochondrial trafficking [15][16][17][18][19] , and LRRK2 regulates lysosomal morphology [20][21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

“…A subset of Rab GTPases, which are master regulators of membrane trafficking 27 , are phosphorylated by LRRK2, and PD-linked LRRK2 mutations increase Rab phosphorylation in cells 9,28 . Phosphorylation of Rabs by LRRK2 is linked to alterations in ciliogenesis [25][26][27] and defects in endolysosomal trafficking 14 . LRRK2 also co-localizes with microtubules in cells and in vitro [29][30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for Parkinson’s Disease-linked LRRK2’s binding to microtubules

Snead

Matyszewski

Dickey

et al. 2022

Preprint

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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-electron microscopy structure of the catalytic half of LRRK2, containing its kinase, which is 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. LRRK1's structure is similar to LRRK2, but LRRK1 does not interact with microtubules. Guided by these structures, we identify amino acids in LRRK2's GTPase domain 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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural basis for Parkinson’s Disease-linked LRRK2’s binding to microtubules

Snead

Matyszewski

Dickey

et al. 2022

Preprint

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“…LRRK2 phosphorylates itself at Serine 1292 (Sheng et al 2012) as well as Serine/Threonine residues in a conserved region of the switch II domain of a subset of Rab GTPases, leading to differential interactions with effector proteins and thus linking LRRK2 to vesicle mediated transport (Steger et al 2016;Bonet-Ponce and Cookson 2019). Likely due to the phosphorylation of Rab GTPases, LRRK2 has been nominated to play important roles at endomembranes including early endosomes, recycling endosomes, late endosomes, and lysosomes (Roosen and Cookson 2016;Hur et al 2019;Yun et al 2015;Bonet-Ponce and Cookson 2021). We and others have previously shown that damage to membranes within the endolysosomal system results in LRRK2 activation as measured by Rab phosphorylation (Bonet-Ponce et al 2020;Herbst et al 2020;Eguchi et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Lysosomal positioning regulates Rab10 phosphorylation at LRRK2-positive lysosomes

Kluss

Beilina

Lewis

et al. 2020

Preprint

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Genetic variation at the Leucine-rich repeat kinase 2 (LRRK2) locus contributes to risk of familial and sporadic Parkinson disease. Recent data have shown a robust association between localization to various membranes of the endolysosomal system and LRRK2 activation. However, the mechanism(s) underlying LRRK2 activation at endolysosomal membranes are still poorly understood. Here we artificially direct LRRK2 to six different membranes within the endolysosomal system. We demonstrate that LRRK2 is activated and able to phosphorylate three of its Rab substrates (Rab10, Rab12 and Rab29) at each compartment. However, we report differing localization of pRab10 and pRab12 at the lysosomal and Golgi membranes. Specifically, we found that pRab10 colocalizes with a sub-population of perinuclear LRRK2-positive Golgi/lysosomal compartments whereas pRab12 localized to all LRRK2-positive Golgi/lysosomal membranes across the cell. When organelle positioning is manipulated by sequestering lysosomes to the perinuclear area, pRab10 colocalization with LRRK2 significantly increases. We also show recruitment of JIP4, a pRab10 effector that we have recently linked to LYTL, after trapping LRRK2 at various membranes. Taken together, we demonstrate that the association of LRRK2 to membranous compartments is sufficient for its activation and Rab phosphorylation independent of membrane identity. Our system also identifies a potential mechanism underlying the distinct relationships between LRRK2 and its substrates Rab10 and Rab12.

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“…However, the most common causes of familial PD are mutations in leucine-rich repeat kinase 2 ( LRRK2 ), and this is a strong risk factor for sporadic disease [ 30 ]. This is a large multi-domain protein (280 kDa) with a GTPase domain, serine/threonine kinase domains, and other domains involved in protein–protein interactions [ 31 ]. This kinase interacts with many molecules, including Rab GTPases.…”

Section: Introduction To Pd Pathogenesismentioning

confidence: 99%

“…Mutations in these domains may lead to a hyperactive protein with toxic effects. LRRK2 plays multiple roles in cells, including in vesicular trafficking, endosomal transport, autophagy, cytoskeleton dynamics, ciliogenesis, neurite growth, mitochondrial morphology, and mitochondrial calcium regulation [ 31 , 32 , 33 , 34 , 35 ]. In nigral neurons, it is specifically involved in vesicle formation and docking, as well as ER-to-Golgi and Golgi-to-membrane transport and the internalization of dopamine receptors at the synapse [ 36 , 37 ].…”

Section: Introduction To Pd Pathogenesismentioning

confidence: 99%

Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson’s Disease

Martı́nez-Menárguez

Martínez‐Alonso

Cara-Esteban

et al. 2021

IJMS

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Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause of cell death is not known but could be due to mitochondrial dysfunction, protein homeostasis failure, and alterations in the secretory/endolysosomal/autophagic pathways. Survival nigral neurons overexpress the small GTPase Rab1. This protein is considered a housekeeping Rab that is necessary to support the secretory pathway, the maintenance of the Golgi complex structure, and the regulation of macroautophagy from yeast to humans. It is also involved in signaling, carcinogenesis, and infection for some pathogens. It has been shown that it is directly linked to the pathogenesis of PD and other neurodegenerative diseases. It has a protective effect against α–σψν toxicity and has recently been shown to be a substrate of LRRK2, which is the most common cause of familial PD and the risk of sporadic disease. In this review, we analyze the key aspects of Rab1 function in dopamine neurons and its implications in PD neurodegeneration/restauration. The results of the current and former research support the notion that this GTPase is a good candidate for therapeutic strategies.

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LRRK2 recruitment, activity, and function in organelles

Cited by 54 publications

References 162 publications

Structural basis for Parkinson’s Disease-linked LRRK2’s binding to microtubules

Structural basis for Parkinson’s Disease-linked LRRK2’s binding to microtubules

Lysosomal positioning regulates Rab10 phosphorylation at LRRK2-positive lysosomes

Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson’s Disease

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