Affinage

LRRK2

Leucine-rich repeat serine/threonine-protein kinase 2 · UniProt Q5S007

Round 2 corrected
Length
2527 aa
Mass
286.1 kDa
Annotated
2026-04-28
130 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRRK2 is a large multidomain ROCO-family enzyme that integrates serine/threonine kinase and GTPase activities to regulate endolysosomal membrane trafficking, autophagy, and neuronal integrity. Its principal physiological substrates are a subset of Rab GTPases (Rab8A, Rab10, Rab12, Rab35 and others), which LRRK2 phosphorylates on a conserved switch-II residue in a reaction that requires GTP-bound Roc domain activity, dimeric assembly, and membrane recruitment to endolysosomal compartments—a process governed by the CASM/GABARAP pathway, lysosomal positioning, and counterbalanced by the phosphatase PPM1H (PMID:26824392, PMID:33177079, PMID:31663853, PMID:36256825, PMID:39812709). Phosphorylated Rabs recruit the motor adaptor JIP4, driving lysosomal tubulation/sorting (LYTL) and modulating autophagosome transport; pathogenic Parkinson disease mutations (G2019S, R1441C/G, Y1699C) increase kinase output or impair GTPase hydrolysis, leading to Rab hyperphosphorylation that disrupts vesicular trafficking, synaptic organization, microglial motility, and chaperone-mediated autophagy (PMID:33177079, PMID:34110246, PMID:23455607, PMID:26365310, PMID:33006315). Mutations in LRRK2 are the most common genetic cause of familial Parkinson disease (PARK8 locus), with gain-of-function kinase activity required for neurotoxicity and amenable to pharmacological inhibition (PMID:15541308, PMID:16750377, PMID:26078453).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2004 High

    Identification of LRRK2 as the PARK8 gene established the first high-confidence causal locus for autosomal-dominant Parkinson disease and revealed its unique multidomain architecture containing both kinase (MAPKKK-class) and Roc GTPase domains.

    Evidence Positional cloning, candidate gene sequencing, and post-mortem neuropathology across dozens of PD families

    PMID:15541308 PMID:15541309

    Open questions at the time
    • No enzymatic characterization yet performed
    • Mechanism linking mutations to neurodegeneration unknown
    • Physiological substrates unidentified
  2. 2006 High

    Demonstrating that PD mutations increase kinase activity and that kinase-dead versions abolish toxicity established a gain-of-function kinase mechanism as the driver of LRRK2-mediated neurodegeneration, while GTPase activity was shown to regulate kinase output.

    Evidence In vitro kinase assays with recombinant LRRK2; kinase-dead and GTPase-dead mutagenesis; neuronal toxicity and neurite length assays in primary neurons and rodent CNS

    PMID:16269541 PMID:16750377 PMID:16980962 PMID:17114044 PMID:17200152

    Open questions at the time
    • Physiological kinase substrates still unknown
    • Mechanism of GTPase-to-kinase signal transduction unclear
    • No structural information on any domain
  3. 2007 High

    Characterization of LRRK2 in C. elegans and Drosophila revealed conserved roles in polarized vesicle sorting and dopaminergic neuron maintenance, placing LRRK2 squarely in the membrane trafficking pathway.

    Evidence C. elegans lrk-1 mutants with synaptic vesicle mis-sorting; Drosophila LRRK loss-of-function with DA neuron degeneration; Drosophila G2019S overexpression with dose-dependent DA neuron loss

    PMID:17346966 PMID:17498648 PMID:18258746

    Open questions at the time
    • Direct mammalian trafficking substrates not identified
    • Mechanism of vesicle sorting regulation unresolved
  4. 2009 High

    Discovery that kinase activity resides with the LRRK2 dimer and that R1441C impairs autophagic balance linked the quaternary structure of LRRK2 to its catalytic regulation and positioned it as a negative regulator of autophagy.

    Evidence Size-exclusion chromatography with kinase activity measurement of separated fractions; autophagic flux assays with LRRK2 knockdown and R1441C expression

    PMID:19770575 PMID:19826009

    Open questions at the time
    • Structural basis of dimerization unknown
    • Autophagic substrates or effectors not identified
  5. 2013 High

    Two parallel discoveries—that LRRK2 is degraded by and inhibits chaperone-mediated autophagy (CMA), and that RAB7L1 genetically interacts with LRRK2 in endolysosomal sorting—converged to define the endolysosomal system as the principal cellular context for LRRK2 function and dysfunction.

    Evidence CMA lysosomal binding assays in iPSC-derived DA neurons, transgenic mice, and PD brain; genetic epistasis of Rab7L1 and LRRK2 in Drosophila and rodent neurons with retromer analysis

    PMID:23395371 PMID:23455607

    Open questions at the time
    • Direct LRRK2-Rab interaction mechanism unknown
    • Retromer connection not mechanistically resolved
  6. 2014 High

    LRRK2 was found to scaffold PKA signaling in striatal neurons, with loss of function or the R1441C mutation causing excessive PKA-mediated phosphorylation of synaptic targets (cofilin, GluR1) and abnormal synaptogenesis, revealing a kinase-independent scaffolding role at synapses.

    Evidence Co-IP of LRRK2 with PKARIIβ; PKA activity assays in Lrrk2-KO and R1441C knock-in mice; synapse imaging

    PMID:24464040

    Open questions at the time
    • Whether PKA scaffolding is independent of or linked to Rab phosphorylation unclear
    • Synaptic phenotype not tested with kinase inhibitors
  7. 2016 High

    Unbiased phosphoproteomics identified a defined subset of Rab GTPases as bona fide LRRK2 substrates phosphorylated on a conserved switch-II residue, fundamentally redefining the LRRK2 signaling pathway and providing the first pharmacodynamic biomarkers for kinase activity.

    Evidence Quantitative phosphoproteomics in KO cells and with LRRK2 inhibitors; in vitro kinase assays; GDI binding assays showing phosphorylation impairs Rab recycling

    PMID:26824392

    Open questions at the time
    • Functional consequences of individual Rab phosphorylation events largely uncharacterized
    • Relative contribution of each Rab substrate to disease unclear
  8. 2019 High

    Two structural milestones—the WD40 domain crystal structure revealing a dimerization interface disrupted by PD variants, and identification of PPM1H as the opposing phosphatase for LRRK2-phosphorylated Rabs—defined the structural basis of kinase regulation and the signaling off-switch.

    Evidence X-ray crystallography of WD40 domain with mutagenesis; unbiased siRNA phosphatase screen identifying PPM1H; in vitro dephosphorylation and cilia formation assays

    PMID:30635421 PMID:31663853

    Open questions at the time
    • Full-length LRRK2 structure not yet determined
    • PPM1H regulation in disease contexts not explored
    • PPM1H-LRRK2 interplay at lysosomes not established
  9. 2020 High

    LRRK2 was shown to be recruited to stressed lysosomes where it phosphorylates Rab10/Rab35 and recruits the motor adaptor JIP4 to drive lysosomal tubulation/sorting (LYTL), establishing the core effector mechanism downstream of Rab phosphorylation; separately, lysosomal positioning was found to regulate LRRK2 activation, and forced membrane recruitment to any endolysosomal compartment was sufficient to activate the pathway.

    Evidence APEX proximity proteomics; super-resolution and FIB-SEM imaging of lysosomal tubules; rapamycin-induced membrane targeting; lysosomal positioning perturbations (ARL8B/RILP); Rab29-KO mice

    PMID:32919031 PMID:33135724 PMID:33177079 PMID:35580815 PMID:36256825

    Open questions at the time
    • Cargo sorted by LYTL tubules not defined
    • Physiological triggers of lysosomal LRRK2 recruitment in neurons incompletely understood
    • Rab29 dispensability conflicts with earlier overexpression data
  10. 2022 High

    Cryo-EM structure of the LRRK2 catalytic half bound to microtubules revealed the GTPase domain mediates microtubule interaction independently of kinase activity, providing the first near-atomic structural framework for understanding LRRK2 filament formation on microtubules seen with pathogenic mutants and Type I kinase inhibitors.

    Evidence Cryo-EM at sub-nanometer resolution; mutagenesis of microtubule-binding residues validated in vitro and in cells

    PMID:36510024

    Open questions at the time
    • Full-length dimeric LRRK2 structure with regulatory domains still lacking
    • Functional significance of microtubule decoration in neurons debated
  11. 2023 High

    Rab12 was identified as a novel upstream modulator that recruits LRRK2 to damaged lysosomes and potentiates local Rab10 phosphorylation, clarifying the feed-forward amplification loop at lysosomes.

    Evidence siRNA screen; lysosome immunopurification; imaging of Rab12 recruitment; validation with LRRK2 R1441G and VPS35 D620N knock-in variants

    PMID:37874617

    Open questions at the time
    • Whether Rab12 is phosphorylated before or after LRRK2 recruitment unclear
    • Redundancy among Rab substrates in recruitment not resolved
  12. 2025 High

    The CASM (conjugation of ATG8 to single membranes) pathway, activated by STING signaling and other lysosomal perturbations, was identified as a major upstream regulator of LRRK2 lysosomal recruitment, with GABARAP specifically mediating LRRK2 membrane engagement.

    Evidence STING agonist treatment; CASM pathway perturbation; GABARAP interaction assays; Rab phosphorylation readouts

    PMID:39812709

    Open questions at the time
    • Structural basis of LRRK2-GABARAP interaction not resolved
    • Whether CASM-LRRK2 axis operates in neurons and microglia in vivo not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of dimeric LRRK2 in active versus autoinhibited states, the identity of cargoes sorted by LYTL tubules, the relative pathogenic contributions of individual Rab substrate phosphorylation events, and whether therapeutic kinase inhibition can reverse disease-relevant phenotypes in humans without adverse effects from on-target lysosomal or pulmonary toxicity.
  • Full-length active/autoinhibited LRRK2 dimer structure missing
  • LYTL tubule cargo identity unknown
  • Therapeutic window for kinase inhibition in humans not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016740 transferase activity 5 GO:0003924 GTPase activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005764 lysosome 7 GO:0031410 cytoplasmic vesicle 3 GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 7 R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 4 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-9612973 Autophagy 4 R-HSA-1643685 Disease 3
Partners
ARFGAP1GABARAPPPM1HRAB10RAB12RAB35RAB8ASPAG9

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 LRRK2 (dardarin) was identified as a novel gene containing missense mutations segregating with PARK8-linked Parkinson's disease, establishing it as the causal gene for this familial PD locus. Positional cloning and candidate gene sequencing in five PD families Neuron High 15541308
2004 LRRK2 encodes a large multifunctional protein belonging to the ROCO family, containing a MAPKKK-class protein kinase domain and a Ras-of-complex (Roc) GTPase domain, with six disease-segregating mutations identified including missense and splice-site variants; post-mortem analysis revealed strikingly diverse neuropathologies (Lewy body PD, diffuse Lewy body disease, nigral degeneration, PSP-like pathology) among mutation carriers. High-resolution recombination mapping, candidate gene sequencing, post-mortem neuropathology in 46 families Neuron High 15541309
2005 PD-associated LRRK2 mutations (G2019S and R1441C) increase kinase activity in vitro, as measured by autophosphorylation and phosphorylation of a generic substrate, without altering protein levels or localization, supporting a gain-of-function mechanism. In vitro kinase assays with full-length recombinant LRRK2; subcellular fractionation showing mitochondrial outer membrane association Proceedings of the National Academy of Sciences of the United States of America High 16269541
2006 Kinase activity is required for the toxic effects of mutant LRRK2: a kinase-dead version of LRRK2 blocks inclusion body formation and strongly delays neuronal cell death caused by pathogenic mutations; LRRK2 protein is expressed in human midbrain neurons and C-terminal epitopes are found in some Lewy bodies. Kinase-dead mutagenesis; neuronal cell death assays; immunocytochemistry in human brain tissue Neurobiology of disease High 16750377
2006 LRRK2 kinase activity is regulated by GTP via the intrinsic GTPase Roc domain; reducing kinase activity of mutant LRRK2 correspondingly reduces neuronal toxicity, establishing that both kinase and GTPase activities are required for neurotoxicity. GTP-binding assays; kinase-dead and GTPase-dead mutagenesis; neuronal toxicity assays Nature neuroscience High 16980962
2006 PD-associated LRRK2 mutations display disinhibited kinase activity and induce progressive reduction in neurite length and branching in primary neurons and in intact rodent CNS; LRRK2 deficiency leads to increased neurite length and branching; mutant LRRK2 neurons harbor phospho-tau-positive lysosomal inclusions and undergo apoptosis. Primary neuronal cultures; in vivo rodent CNS expression; kinase activity assays; immunofluorescence Neuron High 17114044
2007 Seven of ten familial LRRK2 mutations result in increased kinase activity; LRRK2 kinase activity requires GTPase activity, whereas GTPase activity functions independently of kinase activity; both activities are required for neurotoxicity and potentiation of peroxide-induced cell death. In vitro kinase assays; GTPase activity assays; mutagenesis of conserved residues; neuronal toxicity assays Human molecular genetics High 17200152
2007 Purified brain LRRK2 possesses both kinase and GTPase activity (GTP binding and hydrolysis); PD mutations R1441C/G in the GTPase domain cause reduced GTP hydrolysis activity; brain LRRK2 is associated with elevated kinase activity compared to lung or cell-culture LRRK2. Purification of epitope-tagged LRRK2 from transgenic mouse brain; GTP binding and hydrolysis assays; kinase assays Journal of neurochemistry High 17623048
2007 C. elegans LRK-1 (LRRK2 ortholog) is localized in the Golgi apparatus and is required for polarized sorting of synaptic vesicle (SV) proteins to axons by excluding SV proteins from the dendrite-specific AP-1/UNC-101 transport machinery; loss of lrk-1 results in SV proteins localizing to both presynaptic and dendritic endings. C. elegans genetics; deletion mutants; live imaging; epistasis with AP-1 mu1 adaptor UNC-101 and kinesin UNC-104 Current biology : CB High 17346966
2008 Expression of wild-type or G2019S-LRRK2 in Drosophila causes retinal degeneration and adult-onset selective loss of dopaminergic neurons with locomotor dysfunction; G2019S causes more severe parkinsonism-like phenotype than equivalent wild-type LRRK2; L-DOPA improves locomotor impairment but does not prevent dopaminergic neuron loss. GAL4/UAS transgenic Drosophila; dopaminergic neuron counting; locomotor assays; pharmacological rescue Proceedings of the National Academy of Sciences of the United States of America High 18258746
2008 Loss of LRRK (Drosophila LRRK2 ortholog) causes severely impaired locomotor activity and degeneration/shrinkage of dopaminergic neurons (reduced tyrosine hydroxylase immunostaining), demonstrating that LRRK2 is critical for dopaminergic neuron integrity in vivo. Drosophila loss-of-function mutants; locomotor assays; tyrosine hydroxylase immunostaining Biochemical and biophysical research communications High 17498648
2009 LRRK2 kinase activity resides with dimeric LRRK2 rather than monomeric or high-molecular-weight oligomeric forms; disruption of GTPase or kinase activity enhances oligomer formation and prevents dimer formation; pathogenic mutations that increase kinase activity significantly increase the proportion of dimer structures; kinase inhibition by staurosporine ablates LRRK2 dimers. Size-exclusion chromatography/fractionation; kinase activity assays of separated fractions; kinase inhibitor treatment The Journal of biological chemistry High 19826009
2010 LRRK2 binds to MAP kinase kinases MKK3, MKK6, and MKK7, and also binds to JNK-interacting proteins JIP1, JIP2, JIP3, and JIP4; LRRK2 association correlates with increased total JIP1, JIP3, JIP4, oligomeric JIP and ubiquitinated JIP levels, implicating LRRK2 in regulation of the stress kinase cascade. Co-immunoprecipitation; immunoblot analysis of JIP levels Neuro-degenerative diseases Medium 20173330
2012 ArfGAP1 is the first identified GTPase activating protein (GAP) for LRRK2; ArfGAP1 binds LRRK2 predominantly via the WD40 and kinase domains, increases LRRK2 GTPase activity, and regulates LRRK2 toxicity in vitro and in Drosophila; reciprocally, LRRK2 phosphorylates ArfGAP1 and inhibits its GAP activity, while ArfGAP1 reduces LRRK2 autophosphorylation and kinase activity. Co-IP; in vitro GTPase activity assays; in vitro kinase assays; Drosophila toxicity assays; shRNA knockdown The Journal of neuroscience : the official journal of the Society for Neuroscience High 22423108
2013 LRRK2 is degraded in lysosomes by chaperone-mediated autophagy (CMA); the pathogenic G2019S mutant is poorly degraded by CMA; both wild-type and pathogenic mutant LRRK2 interfere with the CMA translocation complex in the presence of other CMA substrates, resulting in defective CMA and self-perpetuating inhibition; this was observed in neuronal cultures, LRRK2 transgenic mouse brain, iPSC-derived dopaminergic neurons, and PD patient brains. Lysosomal binding assays; CMA flux measurements; LRRK2 transgenic mice; iPSC-derived DA neurons; human PD brain tissue analysis Nature neuroscience High 23455607
2013 RAB7L1 (encoded at the PARK16 locus) interacts with LRRK2 and modifies intraneuronal protein sorting; deficiency of RAB7L1 in rodent neurons or its Drosophila ortholog recapitulates degeneration seen with familial LRRK2 mutations; RAB7L1 overexpression rescues LRRK2 mutant phenotypes; PD-associated defects in RAB7L1 or LRRK2 lead to endolysosomal and Golgi sorting defects and deficiency of the VPS35 retromer component. Genetic epistasis in Drosophila and rodent neurons; Co-IP; retromer complex analysis; endolysosomal sorting assays Neuron High 23395371
2014 LRRK2 negatively regulates PKA activity in striatal projection neurons (SPNs) by interacting with PKA regulatory subunit IIβ (PKARIIβ); loss of LRRK2 promotes synaptic translocation of PKA and increases PKA-mediated phosphorylation of cofilin and GluR1, causing abnormal synaptogenesis; the R1441C mutation impairs LRRK2-PKARIIβ interaction, inducing excessive PKA activity. Co-IP of LRRK2 with PKARIIβ; PKA activity assays; phosphorylation of cofilin and GluR1 in Lrrk2-/- and R1441C mice; synaptic translocation imaging Nature neuroscience High 24464040
2015 LRRK2 binds to focal adhesion kinase (FAK) and phosphorylates its Thr-X-Arg/Lys (TXR/K) motifs, attenuating FAK activity (decreased pY397 phosphorylation); G2019S-LRRK2 decreases pY397-FAK levels in brain, microglia, and HEK cells and retards ADP-induced microglial motility; LRRK2 kinase inhibition restores pY397 levels and rescues microglial motility. Co-IP of LRRK2 with FAK; in vitro kinase assays; phosphorylation assays; live-cell motility assays with G2019S transgenic microglia; LRRK2 kinase inhibitor rescue Nature communications High 26365310
2015 LRRK2 kinase inhibition (PF-06447475) is well tolerated in rats and provides neuroprotection against α-synuclein-induced dopaminergic neurodegeneration; G2019S-LRRK2 exacerbates dopaminergic neurodegeneration and inflammation in response to α-synuclein overexpression, and both are mitigated by LRRK2 kinase inhibition. AAV-mediated α-synuclein overexpression in rat substantia nigra; LRRK2 kinase inhibitor treatment; stereological dopaminergic neuron counting; inflammatory marker assessment The Journal of biological chemistry High 26078453
2015 LRRK2 facilitates tau phosphorylation as a scaffold protein rather than as a direct tau kinase; LRRK2 binds tau 140-200-fold more strongly than cdk5 but has 250-480-fold lower specific activity than cdk5 on tau; cdk5 and tau co-immunoprecipitate with endogenous LRRK2; LRRK2 knockdown reduces tau phosphorylation at Ser396/Ser404 without affecting kinase inhibitor-sensitive sites. In vitro kinase assays comparing LRRK2 and cdk5; binding affinity measurements; Co-IP of endogenous LRRK2 with tau and cdk5 in SH-SY5Y cells and mouse brain; LRRK2 siRNA knockdown Biochemistry High 26268594
2016 Phosphoproteomics identified a subset of Rab GTPases (Rab3A/B/C/D, Rab5A/B, Rab8A/B, Rab10, Rab12, Rab29, Rab35, Rab43) as bona fide physiological LRRK2 substrates; LRRK2 directly phosphorylates a conserved Thr/Ser residue in the switch-II domain in vivo and in vitro; pathogenic LRRK2 variants increase Rab phosphorylation; phosphorylation strongly decreases Rab affinity to GDP dissociation inhibitors (GDIs). Quantitative phosphoproteomics; genetics (KO cells); pharmacology (LRRK2 inhibitors); in vitro kinase assays; GDI binding assays eLife High 26824392
2016 LRRK2 negatively regulates α-synuclein clearance by microglia; LRRK2-KO microglia take up and clear α-synuclein more effectively than WT, associated with increased Rab5-positive early endosomes and enhanced Rab5-dynamin 1 interaction, indicating LRRK2 negatively regulates endocytosis. LRRK2-KO mouse microglia; α-synuclein uptake assays; Rab5/Rab7/Rab11 immunostaining; Rab5-dynamin 1 Co-IP BMC neuroscience Medium 27903237
2016 LRRK2 interacts with p62/SQSTM-1, a selective autophagic receptor; p62 overexpression leads to robust degradation of LRRK2 through the autophagy-lysosome pathway; LRRK2 indirectly regulates Ser351 and Ser403 phosphorylation of p62 and reduces p62-Keap1 interaction. Co-IP of LRRK2 with p62; autophagy flux assays; phosphorylation analysis of p62 PloS one Medium 27631370
2017 The structural interface between LRRK2 and 14-3-3 proteins was characterized: phosphorylation of multiple LRRK2 sites (including Ser910/Ser935) enables multivalent 14-3-3 binding; PD-relevant mutations impair this interaction, which is connected to enhanced kinase activity, LRRK2 inclusion body formation, and reduced neurite length. Biochemical binding assays; crystal structures of 14-3-3 bound to LRRK2 phosphopeptides The Biochemical journal High 28202711
2018 LRRK2 kinase activity promotes mitochondrial fission in microglia via Drp1; LPS treatment increases LRRK2 protein levels and mitochondrial fission in microglia; G2019S-LRRK2 transgenic mice show decreased mitochondrial area and reduced microglial processes; LRRK2 kinase inhibition (GSK2578215A) rescues these phenotypes and reduces CD68, Drp1, and TNF-α levels. G2019S transgenic mice; primary microglia; LRRK2 kinase inhibitor treatment; mitochondrial morphology analysis; Drp1 and inflammatory marker quantification Experimental neurobiology Medium 30022868
2019 PPM1H phosphatase acts as a key counterbalance to LRRK2 signaling by selectively dephosphorylating LRRK2-phosphorylated Rab proteins; PPM1H knockout increases endogenous Rab phosphorylation; PPM1H directly and efficiently dephosphorylates Rab8A in biochemical studies; a substrate-trapping PPM1H mutant (Asp288Ala) binds with high affinity to LRRK2-phosphorylated Rabs; PPM1H is localized to the Golgi and its knockdown suppresses primary cilia formation similarly to pathogenic LRRK2. siRNA screen of all human phosphatases; PPM1H KO cells; in vitro dephosphorylation assays; substrate-trapping mutant; Golgi localization imaging; cilia formation assays eLife High 31663853
2019 Crystal structure of the WD40 domain of human LRRK2 at 2.6-Å resolution reveals a seven-bladed WD40 fold that forms dimers in crystal and in solution; PD-associated and structure-based mutations in the WD40 domain (including G2385R) mainly compromise dimer formation; WD40 dimerization-defective mutants including G2385R show enhanced kinase activity as measured by Rab10 phosphorylation. X-ray crystallography; solution measurements of dimerization; phospho-Rab10 kinase activity assays of WD40 mutants Proceedings of the National Academy of Sciences of the United States of America High 30635421
2020 LRRK2 is recruited to lysosomes after lysosome membrane rupture (LLOME exposure) and mediates lysosomal tubulation/sorting (LYTL); LRRK2 recruits motor adaptor JIP4 to lysosomes in a kinase-dependent manner via phosphorylation of RAB35 and RAB10; JIP4 promotes formation of LAMP1-negative tubules that release membranous vesicles from lysosomes. Unbiased proteomic screen (APEX proximity labeling); super-resolution live-cell imaging; FIB-SEM; LRRK2 kinase inhibitors; RAB phosphorylation assays Science advances High 33177079
2020 Lysosomal stress agents (lysosomotropic drugs, nigericin, monensin, chloroquine, LLOMe) potently stimulate LRRK2-dependent Rab10 phosphorylation and promote formation of LRRK2-coated enlarged lysosomes; this upregulation occurs not by increasing LRRK2 enzymatic activity per se but by enhancing molecular proximity between LRRK2 and Rab GTPase substrates on lysosomal surfaces; the effect is downstream of Rab29-mediated LRRK2 activation. Lysosomal stress agent treatment; Rab10 phosphorylation assays; LRRK2 autophosphorylation at Ser1292; proximity measurements; Rab29 KO cells Neurobiology of disease High 32919031
2020 LRRK2-mediated hyperphosphorylation of RAB proteins recruits SPAG9/JIP4 to autophagosomal membranes; increased JIP4 on autophagosomes induces abnormal kinesin-1 recruitment and activation, creating an unproductive tug-of-war between anterograde and retrograde motors that impairs processive autophagosome transport and maturation in axons. Live-cell imaging of autophagosome transport in neurons; G2019S-LRRK2 expression; kinase-dependent rescue; kinesin-1 and JIP4 co-localization assays Autophagy Medium 34110246
2020 Rab29 knockout does not influence basal endogenous LRRK2 activity (Rab10 and Rab12 phosphorylation) in wild-type, R1441C knock-in, or VPS35[D620N] knock-in mice or primary cells; nigericin induces the greatest increase (5-9-fold) in Rab10/Rab12 phosphorylation in a LRRK2 inhibitor-sensitive but Rab29-independent manner. Rab29 KO mice; Rab10/Rab12 phosphorylation assays in brain and fibroblasts; lysosomal stress agents; LRRK2 inhibitors The Biochemical journal High 33135724
2021 Type I LRRK2 inhibitors (binding closed kinase conformation) and Type II inhibitors (binding open conformation) both suppress phosphorylation of Rab10 and Rab12 and promote mitophagy; Type II inhibitors fail to induce dephosphorylation of N-terminal biomarker phosphosites (Ser935), demonstrating that these biomarker sites report on kinase conformation (open vs. closed) rather than catalytic activity per se. Rab10/Rab12 phosphorylation assays; mitophagy assays; Ser935 dephosphorylation; LRRK2[A2016T] resistance mutant validation The Biochemical journal High 34515301
2022 Cryo-EM structure of the catalytic half of LRRK2 (kinase in closed conformation + GTPase domains) bound to microtubules was determined; specific residues in LRRK2's GTPase domain mediate microtubule binding; mutation of these residues disrupts microtubule binding in vitro and in cells without affecting kinase activity; LRRK1, though structurally similar, does not interact with microtubules. Cryo-EM structure determination; in vitro microtubule binding assays; mutagenesis; cell-based co-localization assays Nature structural & molecular biology High 36510024
2022 LRRK2 activation and Rab10 phosphorylation at lysosomes is regulated by lysosomal positioning; anterograde transport of lysosomes to the cell periphery (via ARL8B/SKIP overexpression or JIP4 knockdown) blocks LRRK2-dependent Rab10 recruitment and phosphorylation and prevents LYTL lysosomal tubulation; perinuclear lysosomal clustering (via RILP overexpression) increases LRRK2-dependent Rab10 phosphorylation; PPM1H knockdown significantly increases pRab10 and lysosomal tubulation. Directed LRRK2 localization system; ARL8B/SKIP overexpression; RILP overexpression; JIP4 KD; PPM1H KD; super-resolution imaging of pRab10 and lysosomal tubulation Proceedings of the National Academy of Sciences of the United States of America High 36256825
2022 Directing LRRK2 to any membrane of the endolysosomal pathway (Golgi, lysosomes, plasma membrane, recycling/early/late endosomes) via rapamycin-dependent oligomerization is sufficient to trigger local accumulation of phosphorylated RAB10, RAB12, and JIP4 recruitment, irrespective of membrane identity; endogenous Rab29 is not required for LRRK2 activation at Golgi or lysosomes. Rapamycin-dependent LRRK2 targeting to specific organelles; phospho-RAB10/RAB12 immunofluorescence; JIP4 recruitment; Rab29 KO validation Neurobiology of disease High 35580815
2023 Rab12 is a novel modulator of LRRK2-dependent Rab10 phosphorylation; Rab12 is recruited to damaged lysosomes and drives local LRRK2-dependent increases in Rab10 phosphorylation at the lysosome; PD-linked variants LRRK2 R1441G and VPS35 D620N increase LRRK2 recruitment to lysosomes and elevate lysosomal pT73-Rab10 levels. siRNA screen; lysosome immunopurification; imaging of Rab12 recruitment; Rab10 phosphorylation assays; PD knock-in variants eLife High 37874617
2025 STING signaling activates LRRK2 kinase activity at lysosomes through the CASM (conjugation of ATG8 to single membranes) pathway; multiple stimuli that perturb lysosomal homeostasis converge on CASM to activate LRRK2; LRRK2 lysosome recruitment and kinase activation are highly dependent on interactions with GABARAP (an ATG8 family member) rather than other ATG8 proteins. STING agonist treatment; CASM pathway perturbation; GABARAP interaction assays; LRRK2 lysosome recruitment imaging; Rab phosphorylation as kinase activity readout The Journal of cell biology High 39812709
2014 Mutant LRRK2 (G2019S and R1441C) expression in cortical neurons increases whole-cell current responses to AMPA and NMDA receptor agonists, increases frequency of spontaneous miniature EPSCs, and increases excitatory synapse density; mutant neurons show enhanced vulnerability to synaptic glutamate stress; NMDA receptor antagonist memantine protects against dendrite degeneration caused by mutant LRRK2. Whole-cell voltage clamp in cultured rat cortical neurons; mEPSC recordings; immunofluorescence for PSD95/VGLUT1; pharmacological rescue with memantine Biochimica et biophysica acta Medium 24874075
2015 LRRK2 promotes accumulation of non-monomeric and high-molecular-weight Tau species and increases Tau secretion independently of LRRK2 kinase activity, possibly through impairment of Tau proteasomal degradation; LRRK2 directly interacts with Tau. Co-IP of LRRK2 with Tau; size-exclusion/native PAGE analysis of Tau species; proteasome activity assays; Tau secretion measurement Molecular neurobiology Medium 26014385
2009 The R1441C mutant form of LRRK2 (expressed from a genomic DNA YPet-LRRK2 reporter) induces impaired autophagic balance at the endocytic-autophagic crossroads; conversely, RNAi-induced knockdown of LRRK2 increases autophagic activity, demonstrating that LRRK2 acts as a negative regulator of autophagic activity. Genomic DNA reporter (STEP recombineering); autophagic flux assays; RNAi knockdown Autophagy Medium 19770575
2020 R1441C and G2019S LRRK2 knock-in mutations increase levels and alter nanoscale organization of glutamatergic AMPA receptors at synapses of striatal projection neurons; these mutations decrease frequency of miniature EPSCs and alter dendritic spine nano-architecture, with effects exaggerated in direct pathway SPNs for R1441C. Super-resolution imaging (STORM); biochemical synaptic fractionation; miniature EPSC recordings; two-photon glutamate uncaging eLife High 33006315
2011 LRRK2 mutant iPSC-derived DA neurons show increased expression of oxidative stress-response genes and α-synuclein protein, and are more sensitive to caspase-3 activation and cell death caused by hydrogen peroxide, MG-132, and 6-hydroxydopamine compared to control DA neurons. iPSC generation from G2019S-LRRK2 patients; DA neuron differentiation; transcriptomic analysis; caspase-3 activation; cell death assays Cell stem cell High 21362567

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2004 Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2368 15541309
2008 Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature genetics 2108 18587394
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
2004 Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 1873 15541308
2009 Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nature genetics 1562 19915575
2014 Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nature genetics 1512 25064009
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
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