Luis Bonet‐Ponce

National Institute on Aging

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Mark Cookson

National Institutes of Health

Sara Sáez-Atiénzar

National Institute on Aging

Jillian H. Kluss

Denali Therapeutics (United States)

Alexandra Beilina

National Institute on Aging

Ravindran Kumaran

Abcam (United Kingdom)

Francisco J. Romero

Generalitat Valenciana

Marı́a F. Galindo

University of Castilla-La Mancha

Chad D. Williamson

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Joaquı́n Jordán

University of Castilla-La Mancha

Natalie Landeck

National Institute on Aging

Cooperative Institutions

National Institutes of Health

Genomics England

Biomedical Research Networking Center on Neurodegenerative Diseases

National Institute on Aging

Instituto de Salud Carlos III

University College London

Centro de Investigación Biomédica en Red

Institute on Aging

Universidad de Sevilla

Hospital Universitario Virgen del Rocío

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The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population‐Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight

Movement Disorders (2019)

Sara Bandrés‐Ciga Sarah Ahmed Marya S. Sabir Cornelis Blauwendraat Astrid Adarmes‐Gómez

The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.

Genetic architecture

10.1002/mds.27864

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Citations (57)

Pathogenic mutations in LRRK2 sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Adamantios Mamais Natalie Landeck Rebekah G. Langston Luis Bonet‐Ponce Bradley Smith

Abstract Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson’s disease (PD) while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo . The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a are poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a into lysosomes in cells while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive accumulation of endocytosed transferrin into Rab8a-positive lysosomes leading to a dysregulation of iron transport. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in post-mortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.

LRRK2

Proinflammatory cytokine

10.1101/2020.07.27.219501

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Citations (15)

Preprint Highlight: Detyrosination enrichment on microtubule subsets is established by the interplay between a stochastically acting enzyme and microtubule stability

Molecular Biology of the Cell (2022)

Luis Bonet‐Ponce

Microtubule detyrosination, the post-translational removal of a tyrosine residue on α-tubulin, marks a stable and rare subpopulation of microtubules. Vasohibin (VASH) is the main enzyme responsible for α-tubulin detyrosination and it binds to α-tubulin on polymerized microtubules. However, the dynamics underlying detyrosination remain unknown. The authors use quantitative super-resolution microscopy, single molecule tracking, and computational modeling to explore microtubule detyrosination. VASH engages with microtubules in a stochastic fashion and detyrosination depends on VASH concentration on single microtubules. As VASH accumulation requires microtubule stability, detyrosination occurs via a stabilization-detyrosination feedback mechanism. This work provides important and novel mechanistic insight into microtubule detyrosination and serves as an example for studying other microtubule post-translational modifications essential for cellular homeostasis.

10.1091/mbc.p22-10-1003

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Preprint Highlight: The selective autophagy receptor p62 and the heat shock protein HSP27 facilitate lysophagy via the formation of phase-separated condensates

Molecular Biology of the Cell (2022)

Luis Bonet‐Ponce

Ruptured lysosomes are cleared by lysophagy, a selective form of macroautophagy. Thus lysophagy protects cells against lysosomal cell death, a form of cell death caused by the release of lysosomal proteases to the cytosol from ruptured lysosomes. However, the mechanism underlying this process is still incomplete. Using HeLa cells, rat primary neurons, and human neurons, the authors show that SQSTM1/p62 is a key lysophagy adaptor that forms phase-separated condensates. Mechanistically, p62 oligomerizes but remains in liquid phase to ensure the formation of an autophagosome along the ruptured lysosome. The liquidlike state of p62 is maintained by the small chaperone HSP27. Amyotrophic lateral sclerosis (ALS)-associated mutations in p62 prevent its localization and disrupt lysophagy. These results demonstrate a new role of p62 in lysophagy and implicate lysophagy in the pathobiology of ALS.

Autophagosome

ATG8

Chaperone (clinical)

10.1091/mbc.p22-08-1003

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Membrane targeting activates Leucine-rich repeat kinase 2 with differential effects on downstream Rab activation

Jillian H. Kluss Alexandra Beilina Chad D. Williamson Patrick A. Lewis Mark Cookson

ABSTRACT Genetic variation at the Leucine-rich repeat kinase 2 ( LRRK2 ) locus contributes to risk of familial and sporadic Parkinson’s 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.

LRRK2

Rab

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Colocalization

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Citations (3)

DHA restores VEGF via Nrf2 protection pathway inhibiting oxidative damage in RPE at high glucose levels

Investigative Ophthalmology & Visual Science (2013)

Siv Johnsen‐Soriano Emma Arnal Miguel Flores‐Bellver Luis Bonet‐Ponce Francisco J. Romero

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Autophagy as a Neuroprotective Mechanism Against 3-Nitropropionic Acid-Induced Cell Death

Current topics in neurotoxicity (2015)

Marı́a F. Galindo Sara Sáez-Atiénzar Luis Bonet‐Ponce Joaquı́n Jordán

10.1007/978-3-319-13939-5_8

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Citations (1)

Preprint Highlight: A lysosomal lipid transport pathway that enables cell survival under choline limitation

Molecular Biology of the Cell (2022)

Luis Bonet‐Ponce

Lysosomes maintain cellular homeostasis by clearing macromolecules and recycling their content to support the cell's needs. Lysosomal dysfunction is also a common feature in many human diseases. However, the mechanisms underlying the recycling of many essential metabolites remain unknown. The authors use a creative CRISPR-Cas9 screen to identify proteins involved in choline export from lysosomes to the cytosol. They identified SPNS1, a lysosomal transmembrane protein essential for cell growth under choline-depleted conditions. Targeted lipidomics on isolated lysosomes and isotope tracing revealed that SPNS1 transports lysophosphatidylcholine from lysosomes into the cytosol, where it is re-esterified into phosphatidylcholine. This work defines a new pathway for lysosomal phospholipid egress and provides a reliable new screening method for the identification of novel lysosomal pathways. This preprint has been assigned the following badges: New Hypothesis, New Methods, Cross-Validation. Read the preprint on bioRxiv ( Scharenberg et al., 2022 ): https://doi.org/10.1101/2022.11.27.517422 .

Phosphocholine

TFEB

10.1091/mbc.p22-11-1002

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Make dopamine neurons great again: An exciting new therapeutic option in parkinson's disease

Movement Disorders (2017)

Luis Bonet‐Ponce Andrew Singleton

Neurogenetics

Section (typography)

10.1002/mds.27078

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Citations (2)

Directing LRRK2 to membranes of the endolysosomal pathway triggers RAB phosphorylation and JIP4 recruitment

Neurobiology of Disease (2022)

Jillian H. Kluss Luis Bonet‐Ponce Patrick A. Lewis Mark Cookson

Coding mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene, which are associated with dominantly inherited Parkinson's disease (PD), lead to an increased activity of the encoded LRRK2 protein kinase. As such, kinase inhibitors are being considered as therapeutic agents for PD. It is therefore of interest to understand the mechanism(s) by which LRRK2 is activated during cellular signaling. Lysosomal membrane damage represents one way of activating LRRK2 and leads to phosphorylation of downstream RAB substrates and recruitment of the motor adaptor protein JIP4. However, it is unclear whether the activation of LRRK2 would be seen at other membranes of the endolysosomal system, where LRRK2 has also shown to be localized, or whether these signaling events can be induced without membrane damage. Here, we use a rapamycin-dependent oligomerization system to direct LRRK2 to various endomembranes including the Golgi apparatus, lysosomes, the plasma membrane, recycling, early, and late endosomes. Irrespective of membrane location, the recruitment of LRRK2 to membranes results in local accumulation of phosphorylated RAB10, RAB12, and JIP4. We also show that endogenous RAB29, previously nominated as an activator of LRRK2 based on overexpression, is not required for activation of LRRK2 at the Golgi nor lysosome. We therefore conclude that LRRK2 signaling to RAB10, RAB12, and JIP4 can be activated once LRRK2 is accumulated at any cellular organelle along the endolysosomal pathway.

LRRK2

Rab

Organelle

10.1016/j.nbd.2022.105769

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Citations (31)