Affinage

LRRK2

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

Length
2527 aa
Mass
286.1 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRRK2 is a large dual-enzyme protein integrating GTPase (ROC-COR) and serine/threonine kinase activities, in which kinase function requires the GTPase domain and PD-linked ROC mutations (R1441C/G) impair GTP hydrolysis (PMID:17623048); LRRK2 also autophosphorylates its own ROC domain to enhance GTP hydrolysis and promote ROC dimerization, coupling its two catalytic modules (PMID:26396237). Its principal signaling output is phosphorylation of a defined set of Rab GTPases—Rab10, Rab12, and Rab35—an activity selectively elevated in idiopathic PD substantia nigra dopamine neurons through an oxidative mechanism with downstream mitochondrial and lysosomal consequences (PMID:30045977), and enhanced by the gain-of-function G2019S kinase mutation (PMID:30150626). LRRK2 is recruited to and activated on endolysosomal membranes: membrane targeting to essentially any endolysosomal compartment is sufficient to trigger local Rab10/Rab12 phosphorylation and JIP4 recruitment (PMID:35580815), with damaged-lysosome recruitment driven by Rab12 (PMID:37874617) and by STING-CASM signaling acting selectively through GABARAP-family ATG8 proteins (PMID:39812709). Phospho-Rab effectors execute distinct cellular programs: phospho-Rab10/35 recruit the motor adaptor JIP4 to drive LYsosomal Tubulation/sorting (LYTL) (PMID:33177079), and phospho-Rab10 recruits RILPL2/Myosin Va to the pericentriolar region to block ciliogenesis (PMID:33727250). LRRK2 kinase activity also disrupts processive axonal autophagosome transport via SPAG9/JIP4-driven aberrant kinesin-1 recruitment (PMID:34110246), regulates macropinosome recycling and PI3K-Akt immune responses in myeloid cells through phospho-Rab10 (PMID:32853409), and modulates α-synuclein propagation via Rab35 (PMID:30150626). Beyond Rab substrates, LRRK2 phosphorylates FAK to attenuate microglial motility (PMID:26365310) and NSF to promote toxic aggregation (PMID:33876242), and negatively regulates PKA signaling in striatal projection neurons by binding PKARIIβ (PMID:24464040). LRRK2 stability is governed by phosphorylation of N-terminal sites (e.g. Ser910/935) that recruit 14-3-3 through a multivalent interface (PMID:28202711); dephosphorylation—triggered by PD mutations, kinase inhibitors, or 14-3-3 disruption—leads to K48/K63 ubiquitination and degradation (PMID:25939886). Structurally, the closed-kinase catalytic half binds microtubules through defined GTPase-domain residues independently of kinase activity (PMID:36510024). In model organisms LRRK2 orthologs are required for dopaminergic neuron integrity (PMID:17498648) and Golgi-based polarized sorting of synaptic vesicle proteins (PMID:17346966).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2007 High

    Established that LRRK2 is a bifunctional enzyme whose kinase activity depends on its GTPase domain and whose GTP hydrolysis is reduced by PD-linked ROC mutations, defining the molecular architecture for all later signaling work.

    Evidence In vitro GTP binding/hydrolysis assays on purified brain and cell-derived LRRK2 with domain-deletion and R1441C/G constructs

    PMID:17623048

    Open questions at the time
    • Did not identify physiological kinase substrates
    • Mechanism coupling GTPase state to kinase output not resolved
  2. 2007 High

    Ortholog genetics linked LRRK2 to neuronal membrane trafficking and dopaminergic neuron survival, providing the first in vivo functional context.

    Evidence C. elegans lrk-1 deletion with SV-protein sorting/epistasis and Drosophila LRRK loss-of-function with TH staining and locomotor assays

    PMID:17346966 PMID:17498648

    Open questions at the time
    • Molecular substrates underlying sorting/survival defects unknown
    • Connection between Golgi sorting role and kinase activity not established
  3. 2014 High

    Identified a kinase-independent role through which LRRK2 restrains PKA signaling at striatal synapses, showing LRRK2 acts via protein-protein interaction as well as catalysis.

    Evidence Reciprocal Co-IP with PKARIIβ, LRRK2 KO and R1441C knock-in mice, PKA activity and cofilin/GluR1 phosphorylation assays

    PMID:24464040

    Open questions at the time
    • How R1441C specifically weakens PKARIIβ binding not structurally defined
    • Relationship to kinase-substrate pathway unclear
  4. 2015 High

    Resolved how LRRK2 stability is regulated, linking N-terminal phosphorylation and 14-3-3 binding to ubiquitin-dependent degradation, explaining why PD mutations and inhibitors destabilize LRRK2.

    Evidence Kinase inhibitor (GNE1023) and PD-mutant studies with K48/K63 ubiquitination assays and calyculin A phosphatase rescue in cells and mice

    PMID:25939886

    Open questions at the time
    • Identity of the relevant phosphatase and E3 ligase not defined
    • Upstream kinases for Ser935 not identified here
  5. 2015 High

    Showed LRRK2 autophosphorylates its ROC domain to accelerate GTP hydrolysis and drive dimerization, providing an intramolecular feedback link between its two enzymatic activities.

    Evidence In vitro kinase and GTP hydrolysis kinetics on purified ROC, size-exclusion dimerization, structural modeling, ROCO4 cross-phosphorylation

    PMID:26396237

    Open questions at the time
    • In vivo relevance of ROC autophosphorylation not established
    • How dimerization relates to membrane activation unknown
  6. 2015 Medium

    Expanded the LRRK2 substrate repertoire beyond Rabs by identifying FAK and Tau as effectors with distinct dependence on kinase activity.

    Evidence Co-IP and in vitro kinase assays (FAK TXR/K phosphorylation; pY397 readouts) plus Tau fractionation and proteasomal degradation assays with kinase-dead mutant

    PMID:26014385 PMID:26365310

    Open questions at the time
    • FAK and Tau effects characterized in separate contexts without unifying pathway
    • Tau interaction is single-lab Co-IP without structural detail
  7. 2017 High

    Provided structural definition of the multivalent 14-3-3:LRRK2 phosphopeptide interface and connected its disruption to kinase hyperactivation and toxicity.

    Evidence Crystal structures of 14-3-3 with LRRK2 phosphopeptides plus biochemical binding and cellular phenotype assays

    PMID:28202711

    Open questions at the time
    • Structures use isolated phosphopeptides, not full-length LRRK2
    • Causal order between 14-3-3 loss and kinase activation not fully resolved
  8. 2018 High

    Demonstrated that wild-type LRRK2 kinase activity is pathologically elevated in human idiopathic PD dopamine neurons via oxidation, extending LRRK2 relevance beyond familial mutations.

    Evidence Proximity ligation assays for pSer1292-LRRK2 and 14-3-3 dissociation in human iPD tissue and rat models with Rab10 phosphorylation and organelle assays

    PMID:30045977

    Open questions at the time
    • Precise oxidative trigger of activation not defined
    • Causal link between pRab10 and mitochondrial/lysosomal defects correlative
  9. 2018 High

    Connected LRRK2 kinase activity to α-synuclein propagation through Rab35, linking the kinase axis to a core PD pathology.

    Evidence Cell, C. elegans epistasis (constitutively active RAB35 rescue), and rodent synucleinopathy models with kinase inhibitor and Rab35 phosphorylation assays

    PMID:30150626

    Open questions at the time
    • Molecular step from pRab35 to propagation not defined
    • Effector downstream of Rab35 in this context unidentified
  10. 2020 High

    Defined the LYTL pathway, establishing that LRRK2 acts at damaged lysosomes via phospho-Rab10/35-dependent JIP4 recruitment to drive membrane tubulation.

    Evidence Unbiased lysosomal proteomic screen, Co-IP, super-resolution and FIB-SEM imaging, kinase inhibition, Rab phosphorylation assays after LLOMe

    PMID:33177079

    Open questions at the time
    • Cargo selectivity of LYTL tubules not defined
    • Physiological/in vivo consequences of LYTL unresolved
  11. 2020 High

    Placed LRRK2 in innate immune trafficking by showing phospho-Rab10 stalls macropinosome recycling to enable PI3K-Akt signaling in myeloid cells.

    Evidence Primary mouse/human macrophage, DC, and microglia cultures with kinase inhibition, Rab10 knockdown, EHBP1L1 overexpression, and chemotaxis/Akt readouts

    PMID:32853409

    Open questions at the time
    • Relationship to neuronal LRRK2 functions unclear
    • In vivo immune consequences not established here
  12. 2020 High

    Showed endogenous Rab29 is dispensable for basal and stress-induced LRRK2 activity, correcting the model that Rab29 is the obligate physiological activator.

    Evidence Rab29 KO crossed into LRRK2/VPS35 knock-in mice with pRab10/pRab12 quantification and endolysosomal stress agents

    PMID:33135724

    Open questions at the time
    • Identity of the genuine physiological activators left open at this stage
    • Possible context-specific Rab29 roles not excluded
  13. 2021 High

    Defined the molecular basis of LRRK2-driven ciliogenesis block, showing phospho-Rab10 recruits RILPL2/Myosin Va to the mother centriole.

    Evidence Co-IP, binding-domain mapping, FLIP microscopy of Myosin Va dynamics, and ciliogenesis assays in RPE cells with pathogenic LRRK2

    PMID:33727250

    Open questions at the time
    • In vivo significance of ciliogenesis defect for PD unresolved
    • Tissue specificity of the effect unclear
  14. 2021 Medium

    Linked hyperactive LRRK2 to defective axonal autophagosome transport via SPAG9/JIP4-driven motor imbalance.

    Evidence Live-cell imaging of autophagosome transport in G2019S neurons with kinase inhibition and motor-recruitment assays

    PMID:34110246

    Open questions at the time
    • Single-lab live-imaging model
    • Direct Rab-to-JIP4 step on autophagosomes not biochemically isolated
  15. 2021 Medium

    Identified NSF as a G2019S substrate whose phosphorylation drives toxic aggregation reversible by autophagy.

    Evidence In vitro kinase assay, human PD tissue immunohistochemistry, and autophagy-induction rescue in G2019S BAC mice with behavioral readouts

    PMID:33876242

    Open questions at the time
    • NSF phosphosite-to-aggregation mechanism not fully defined
    • Single-lab finding
  16. 2021 High

    Used Type I vs Type II inhibitors to distinguish conformational from catalytic readouts, clarifying that Ser935 biomarker sites report kinase conformation rather than activity per se.

    Evidence Comparative inhibitor pharmacology with pRab10/pRab12 and pSer935 assays, mitophagy readouts, and A2016T resistance mutant

    PMID:34515301

    Open questions at the time
    • Structural basis of conformation-coupled Ser935 phosphorylation not solved here
    • In vivo translation of mitophagy effect not established
  17. 2022 High

    Provided the cryo-EM basis for LRRK2-microtubule binding, mapping GTPase-domain residues that mediate the interaction independently of kinase activity.

    Evidence Cryo-EM of the LRRK2 catalytic half on microtubules with mutagenesis validation in vitro and in cells and LRRK1 negative control

    PMID:36510024

    Open questions at the time
    • Functional consequence of microtubule binding for trafficking/signaling unresolved
    • Full-length filament architecture context-dependent
  18. 2022 High

    Showed that LRRK2 activation is spatially encoded—membrane recruitment to any endolysosomal compartment suffices, and lysosomal positioning selectively tunes Rab10 phosphorylation and LYTL.

    Evidence Rapamycin-induced organelle targeting, lysosome positioning manipulations (ARL8B/SKIP, RILP, JIP4 knockdown), PPM1H knockdown, and pRab10/pRab12 imaging in Rab29 KO cells

    PMID:35580815 PMID:36256825

    Open questions at the time
    • Endogenous signals dictating membrane recruitment not fully enumerated here
    • Why Rab10 but not Rab12 is position-restricted mechanistically open
  19. 2023 High

    Identified Rab12 as a damaged-lysosome recruiter that locally amplifies LRRK2-dependent Rab10 phosphorylation, with PD variants increasing lysosomal LRRK2.

    Evidence Targeted siRNA screen, immunopurified lysosome assays, Rab12 recruitment and pRab10 quantification in LRRK2 R1441G and VPS35 D620N knock-in models

    PMID:37874617

    Open questions at the time
    • How Rab12 mechanistically recruits LRRK2 not fully defined
    • Relationship between Rab12 pathway and CASM/STING pathway unresolved
  20. 2023 Medium

    Extended LRRK2 signaling to mitochondrial quality control in kidney, showing an MKK4/JNK-MFN2 degradation axis driving fragmentation.

    Evidence LRRK2 overexpression in human PTCs with MFN2 pSer27/ubiquitination assays and LRRK2 KO/inhibitor rescue in acute kidney injury mice

    PMID:37633049

    Open questions at the time
    • Directness of LRRK2-to-MFN2 phosphorylation versus MKK4/JNK intermediary not fully separated
    • Relevance to neuronal LRRK2 biology unclear
  21. 2025 High

    Connected innate immune STING signaling to LRRK2 activation through the CASM pathway, identifying GABARAP-family ATG8 proteins as the selective recruiter.

    Evidence STING activation and CASM perturbation with lysosomal recruitment, kinase activity (pRab) readouts, and GABARAP vs LC3 dependency tests

    PMID:39812709

    Open questions at the time
    • Structural basis of LRRK2-GABARAP recognition not defined
    • Integration with Rab12-dependent recruitment unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple converging activation inputs (Rab12, STING-CASM-GABARAP, lysosomal damage, oxidation) are integrated at the membrane to set LRRK2 kinase output, and how this maps to selective dopaminergic vulnerability in PD, remains unresolved.
  • No unified model linking recruitment signals to graded kinase activation
  • Mechanism of cell-type-selective neurodegeneration not established
  • Full-length structural basis of membrane-bound active LRRK2 not solved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016740 transferase activity 5 GO:0003924 GTPase activity 2 GO:0008092 cytoskeletal protein binding 1 GO:0098772 molecular function regulator activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005764 lysosome 5 GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
14-3-3JIP4MYO5APRKAR2BRAB10RAB12RAB35RILPL2

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 LRRK2 possesses both kinase and GTPase activity. Purified brain LRRK2 binds and hydrolyzes GTP. PD mutations R1441C/G in the GTPase (ROC) domain reduce GTP hydrolysis activity. GTPase activity of LRRK2 can function independently of kinase activity, whereas kinase activity requires the presence of the GTPase domain. In vitro GTP binding and hydrolysis assays using purified LRRK2 from transgenic mouse brain and transfected cell cultures; domain deletion constructs Journal of neurochemistry High 17623048
2007 C. elegans LRK-1 (LRRK2 ortholog) localizes to the Golgi apparatus and is required for polarized sorting of synaptic vesicle (SV) proteins to axons. In lrk-1 deletion mutants, SV proteins mislocalize to dendrites. This mislocalization depends on the AP-1 µ1 adaptor UNC-101 (dendritic transport) but not on UNC-104 kinesin (axonal transport), placing LRK-1 upstream of the dendritic sorting machinery at the Golgi. C. elegans genetics; lrk-1 deletion mutants; in vivo imaging of fluorescently tagged SV proteins; epistasis with unc-101 and unc-104 mutants; immunolocalization of LRK-1 to Golgi Current biology : CB High 17346966
2007 Loss of Drosophila LRRK (sole ortholog of human LRRK2) causes degeneration of dopaminergic neurons (reduced tyrosine hydroxylase staining, shrunken morphology) and severely impaired locomotor activity, establishing an in vivo requirement for LRRK2 in dopaminergic neuron integrity. Drosophila loss-of-function mutants (LRRK deletion); tyrosine hydroxylase immunostaining; locomotor behavioral assays Biochemical and biophysical research communications Medium 17498648
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 PD-linked R1441C mutation impairs LRRK2–PKARIIβ interaction, leading to excessive PKA activity. Co-immunoprecipitation; LRRK2 knockout mice; PKA activity assays; phosphorylation assays for cofilin and GluR1; synaptic fractionation; R1441C knock-in mice Nature neuroscience High 24464040
2015 LRRK2 kinase inhibition leads to dephosphorylation of Ser935 followed by ubiquitination (via K48 and K63 linkages) and degradation of LRRK2. PD mutations (R1441G, Y1699C, I2020T) and disruption of 14-3-3 binding (via difopein) also cause LRRK2 dephosphorylation and hyper-ubiquitination. Phosphatase activity is directly required for inhibitor/mutant-induced ubiquitination (calyculin A treatment prevents both dephosphorylation and increased ubiquitination). LRRK2 kinase inhibitor treatment (GNE1023); phosphorylation and stability assays in cells and mouse dosing studies; ubiquitination assays (K48/K63 linkage); PD mutant expression; difopein expression; phosphatase inhibitor calyculin A The Biochemical journal High 25939886
2015 LRRK2 autophosphorylates its own ROC (GTPase) domain, and this phosphorylation enhances GTP hydrolysis rate (~2-fold). Phosphorylation also promotes ROC dimer formation and induces conformational changes at the p-loop. The ameba LRRK2 ortholog ROCO4 can phosphorylate human LRRK2 ROC on the same residues as human LRRK2 kinase. In vitro kinase assay with purified ROC domain; GTP hydrolysis kinetics (kcat measurement); GDP/GTP dissociation kinetics; size-exclusion chromatography for dimerization; structural modeling; phosphoproteomics alignment FASEB journal High 26396237
2017 14-3-3 proteins bind LRRK2 at multiple phosphorylated serine residues in a multivalent interaction. Crystal structures of 14-3-3 with LRRK2 phosphopeptides characterize this structural interface. PD-relevant mutations impair 14-3-3 binding, which is linked to enhanced LRRK2 kinase activity, LRRK2 ubiquitination, inclusion body accumulation, and reduced neurite length. Biochemical binding assays; X-ray crystal structures of 14-3-3 with LRRK2 phosphopeptides The Biochemical journal High 28202711
2018 Wild-type LRRK2 kinase activity is selectively enhanced in substantia nigra dopamine neurons in idiopathic PD (iPD) patients and rat models through an oxidative mechanism, resulting in phosphorylation of the LRRK2 substrate Rab10 and downstream abnormalities in mitochondrial protein import and lysosomal function. Proximity ligation assays (PLA) for pSer1292-LRRK2 and LRRK2/14-3-3 dissociation; postmortem human iPD brain tissue; rat PD models; Rab10 phosphorylation assays; mitochondrial import and lysosomal function assays Science translational medicine High 30045977
2018 LRRK2 modulates α-synuclein propagation in a kinase activity-dependent manner via phosphorylation of RAB35. The PD-linked G2019S mutation (increased kinase activity) enhances α-synuclein propagation efficiency. Constitutive RAB35 activation rescues the reduced α-synuclein propagation phenotype in lrk-1 C. elegans mutants (epistasis). LRRK2 kinase inhibition in mice reduces α-synuclein aggregation and enhances lysosomal degradation of α-synuclein. Cell culture, C. elegans, and rodent models; kinase inhibitor treatment; RAB35 phosphorylation assays; lrk-1 mutant epistasis with constitutively active RAB35; in vivo mouse synucleinopathy model with LRRK2 inhibitor Nature communications High 30150626
2020 LRRK2 is recruited to lysosomes after lysosomal membrane damage (LLOMe treatment) and phosphorylates RAB35 and RAB10, which recruits the motor adaptor protein JIP4 to the lysosomal membrane in a kinase-dependent manner. JIP4 then promotes the formation of LAMP1-negative membranous tubules that release vesicular content from lysosomes — a process named LYTL (LYsosomal Tubulation/sorting driven by LRRK2). Unbiased proteomic screen for LRRK2 partners at lysosomal membrane; Co-IP; super-resolution live-cell imaging; FIB-SEM; kinase inhibitor treatments; RAB phosphorylation assays Science advances High 33177079
2020 LRRK2 phosphorylates cytoplasmic PI(3,4,5)P3-positive GTP-Rab10 before EEA1/Rab5 recruitment to macropinosomes, and LRRK2-phosphorylated Rab10 blocks EHBP1L1-mediated recycling tubules from macropinosomes. This stalls fast vesicle recycling to promote PI3K-Akt immunological responses (CCR5-loaded signaling endosomes, Akt activation, chemotaxis) in macrophages, dendritic cells, and microglia. Mouse and human primary macrophage/DC/microglia cultures; LRRK2 kinase inhibitor treatment; Rab10 knockdown; EHBP1L1 overexpression; endocytosis assays (macropinocytosis, phagocytosis, clathrin-mediated); live-cell imaging; Akt and chemotaxis functional assays The EMBO journal High 32853409
2020 Endogenous Rab29 knockout does not influence basal LRRK2 activity (measured by Rab10 and Rab12 phosphorylation) in wild-type, LRRK2[R1441C], or VPS35[D620N] knock-in mouse tissues or primary cells. Stimulation of Rab10/Rab12 phosphorylation by endolysosomal stressors (nigericin, monensin, chloroquine, LLOMe) is suppressed by LRRK2 inhibitors but not blocked by Rab29 deficiency. Rab29 knockout mice; LRRK2/VPS35 knock-in mice; phospho-Rab10 and phospho-Rab12 quantification in brain extracts and primary cells; LRRK2 inhibitor treatment; endolysosomal stress agents The Biochemical journal High 33135724
2021 LRRK2-phosphorylated Rab10 recruits both RILPL2 and Myosin Va to the peri-centriolar region via high-affinity binding to the Myosin Va globular tail domain. In the presence of pathogenic LRRK2, phosphoRab10 retains Myosin Va at pericentriolar membranes (demonstrated by FLIP microscopy) and RILPL2/MyoVa relocalization to the mother centriole blocks ciliogenesis. Co-immunoprecipitation; fluorescence loss in photobleaching (FLIP) microscopy; overexpression of pathogenic LRRK2; RILPL2 overexpression; ciliogenesis assay in RPE cells; binding domain mapping Life science alliance High 33727250
2021 Hyperactive LRRK2 (G2019S mutation) disrupts processive axonal autophagosome transport in neurons in a kinase-dependent manner by recruiting the motor adaptor SPAG9/JIP4 to autophagosomal membranes. Increased SPAG9/JIP4 induces abnormal kinesin-1 recruitment and activation, producing a tug-of-war between anterograde and retrograde motors. This transport disruption correlates with defective autophagosome maturation. Live-cell imaging of autophagosome transport in neurons; LRRK2 G2019S expression; kinase inhibitor treatment; SPAG9/JIP4 recruitment assays; motor protein activity assays; maturation assays Autophagy Medium 34110246
2021 LRRK2 G2019S kinase activity phosphorylates NSF (N-ethylmaleimide sensitive factor) and induces its accumulation in toxic aggregates. NSF aggregates were observed in basal ganglia of G2019S PD patients and in cellular/animal G2019S models. Autophagy induction clears NSF aggregation and rescues motor/cognitive impairment in aged hG2019S BAC mice. In vitro kinase assay demonstrating LRRK2 phosphorylates NSF; immunohistochemistry in human PD brain tissue; cell and BAC mouse models; autophagy induction rescue experiments; behavioral assays Brain : a journal of neurology Medium 33876242
2021 Type I LRRK2 inhibitors (GSK3357679A, MLi-2) and Type II inhibitors (GZD-824, Rebastinib, Ponatinib) both suppress phosphorylation of Rab10 and Rab12 and promote mitophagy. Type II inhibitors do not induce dephosphorylation of LRRK2 N-terminal biomarker sites (e.g., Ser935), indicating these biomarker sites report on the open vs. closed kinase conformation rather than purely on catalytic activity. The A2016T resistance mutation confers cross-resistance to both Type I and Type II inhibitors. Pharmacological comparison of Type I and II inhibitors; pRab10/pRab12 phosphorylation assays; pSer935 and related site assays; mitophagy assays; LRRK2[A2016T] resistance mutant The Biochemical journal High 34515301
2022 Cryo-EM structure of the LRRK2 catalytic half (kinase in closed conformation + GTPase domain) bound to microtubules identifies GTPase domain residues mediating microtubule binding. Mutagenesis of these residues disrupts microtubule binding in vitro and in cells without affecting kinase activity. LRRK1 (closely related) has a similar overall structure but does not interact with microtubules. Cryo-EM structure of LRRK2 catalytic half bound to microtubules; comparative structure of LRRK1; site-directed mutagenesis of GTPase residues; in vitro microtubule-binding assay; cell-based microtubule co-localization Nature structural & molecular biology High 36510024
2022 LRRK2 activation at lysosomes and the phosphorylation of Rab10 (but not Rab12) is restricted to perinuclear lysosomes by lysosomal positioning. Anterograde lysosome transport (via ARL8B/SKIP overexpression or JIP4 knockdown) blocks Rab10 recruitment and phosphorylation by LRRK2 and prevents LYTL tubulation. Conversely, perinuclear lysosomal clustering (via RILP overexpression) increases LRRK2-dependent Rab10 phosphorylation. Phosphatase PPM1H knockdown increases pRab10 signal and lysosomal tubulation in the perinuclear region. Rapamycin-dependent LRRK2 recruitment to lysosomes; ARL8B/SKIP overexpression; JIP4 knockdown; RILP overexpression; pRab10 and pRab12 quantification by immunofluorescence; PPM1H siRNA knockdown; live-cell imaging 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-induced oligomerization is sufficient to trigger local phosphorylation of RAB10, RAB12, and recruitment of JIP4, independent of endogenous RAB29. Rapamycin-dependent organelle-targeting system; pRAB10 and pRAB12 immunofluorescence; JIP4 recruitment assay; RAB29 knockout cells Neurobiology of disease High 35580815
2023 Rab12 acts as a novel regulator of LRRK2 activity at lysosomes. Rab12 is recruited to damaged lysosomes and promotes a local, LRRK2-dependent increase 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. Targeted siRNA screen; imaging and immunopurification of isolated lysosomes; Rab12 recruitment assays; pRab10 quantification at lysosomes; LRRK2 R1441G and VPS35 D620N knock-in models eLife High 37874617
2023 LRRK2 promotes MFN2 degradation via LRRK2-MKK4/JNK-dependent phosphorylation of MFN2 at Ser27, followed by ubiquitination-mediated MFN2 degradation. This leads to mitochondrial fragmentation and increased ROS in proximal renal tubular cells. LRRK2 knockout prevents MFN2 loss and mitochondrial damage in acute kidney injury models. LRRK2 overexpression in human PTCs; MFN2 phosphorylation (pSer27) assays; ubiquitination assays; LRRK2 KO mice in AKI model; mitochondrial morphology analysis; ROS measurement; in vivo LRRK2 inhibitor pretreatment Redox biology Medium 37633049
2025 STING signaling activates LRRK2 kinase activity and recruits it to lysosomes via the CASM (conjugation of ATG8 to single membranes) pathway. Multiple lysosome-perturbing stimuli (beyond STING) converge on CASM to activate LRRK2. LRRK2 lysosomal recruitment and kinase activation are highly dependent on interactions with the GABARAP subfamily of ATG8 proteins, not other ATG8 family members. STING activation assays; CASM pathway perturbation; lysosomal recruitment assays; LRRK2 kinase activity assays (pRab readout); selective GABARAP vs. LC3 dependency experiments The Journal of cell biology High 39812709
2015 LRRK2 binds focal adhesion kinase (FAK) and phosphorylates FAK at its Thr-X-Arg/Lys (TXR/K) motif(s), reducing FAK autophosphorylation at Y397 and attenuating FAK activity. The G2019S-LRRK2 mutation decreases pY397-FAK levels in brain, microglia, and HEK cells, resulting in impaired microglial motility and delayed isolation of injury sites. LRRK2 kinase inhibitor restores pY397 and rescues microglial motility. Co-immunoprecipitation of LRRK2 and FAK; in vitro kinase assay (pTXR/K phosphorylation); pY397-FAK quantification in G2019S transgenic mice brain and microglia; microglial motility assays; LRRK2 kinase inhibitor rescue Nature communications High 26365310
2015 LRRK2 interacts with Tau and promotes accumulation of non-monomeric and high-molecular weight Tau species independent of LRRK2 kinase activity. LRRK2 increases Tau secretion, possibly through impairment of Tau proteasomal degradation. Co-immunoprecipitation of LRRK2 and Tau; biochemical fractionation of Tau species (HMW); proteasomal degradation assays; kinase-dead LRRK2 mutant Molecular neurobiology Medium 26014385
2020 LRRK2 pathogenic mutations (R1441C, G2019S) reshape glutamatergic synapse structure and function in striatal SPNs: increased levels and altered nanoscale organization of AMPA receptors, decreased frequency of miniature EPSCs, and altered dendritic spine nano-architecture. Effects are pathway-specific (exaggerated in direct pathway dSPNs for R1441C). Biochemical synaptic preparations; super-resolution imaging; electrophysiology (mEPSC recording); two-photon glutamate uncaging; R1441C and G2019S knock-in mice; pathway-specific SPN identification eLife Medium 33006315

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 LRRK2 activation in idiopathic Parkinson's disease. Science translational medicine 392 30045977
2020 LRRK2 in Parkinson disease: challenges of clinical trials. Nature reviews. Neurology 367 31980808
2005 Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain : a journal of neurology 254 16272164
2005 An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Annals of neurology 218 15880653
2020 LRRK2 mediates tubulation and vesicle sorting from lysosomes. Science advances 204 33177079
2007 Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants. Journal of neurochemistry 200 17623048
2014 The role of the LRRK2 gene in Parkinsonism. Molecular neurodegeneration 181 25391693
2019 LRRK2 links genetic and sporadic Parkinson's disease. Biochemical Society transactions 169 30837320
2015 Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration. The Journal of biological chemistry 169 26078453
2014 LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity. Nature neuroscience 169 24464040
2016 LRRK2 at the interface of autophagosomes, endosomes and lysosomes. Molecular neurodegeneration 144 27927216
2007 LRK-1, a C. elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins. Current biology : CB 139 17346966
2018 The Role of LRRK2 in Neurodegeneration of Parkinson Disease. Current neuropharmacology 136 29473513
2015 Cellular processes associated with LRRK2 function and dysfunction. The FEBS journal 135 25899482
2014 LRRK2 pathobiology in Parkinson's disease. Journal of neurochemistry 131 25251388
2010 LRRK2 and Parkinson disease. Archives of neurology 128 20457952
2007 Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. Biochemical and biophysical research communications 126 17498648
2017 Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Experimental neurology 125 28764903
2019 LRRK2 regulation of immune-pathways and inflammatory disease. Biochemical Society transactions 123 31769472
2022 LRRK2 and idiopathic Parkinson's disease. Trends in neurosciences 122 34991886
2018 LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation. Nature communications 122 30150626
2007 Dynamic and redundant regulation of LRRK2 and LRRK1 expression. BMC neuroscience 121 18045479
2020 "LRRK2: Autophagy and Lysosomal Activity". Frontiers in neuroscience 114 32523507
2013 LRRK2: cause, risk, and mechanism. Journal of Parkinson's disease 113 23938341
2012 Brain Penetrant LRRK2 Inhibitor. ACS medicinal chemistry letters 107 23066449
2018 LRRK2 and mitochondria: Recent advances and current views. Brain research 104 29894679
2015 LRRK2 Pathways Leading to Neurodegeneration. Current neurology and neuroscience reports 104 26008812
2016 Nrf2 mitigates LRRK2- and α-synuclein-induced neurodegeneration by modulating proteostasis. Proceedings of the National Academy of Sciences of the United States of America 102 28028237
2008 Familial parkinsonism: study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes. Parkinsonism & related disorders 93 18804399
2015 LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase. Nature communications 90 26365310
2020 LRRK2 and the Endolysosomal System in Parkinson's Disease. Journal of Parkinson's disease 87 33044192
2020 Pathological Functions of LRRK2 in Parkinson's Disease. Cells 80 33266247
2014 LRRK2, a puzzling protein: insights into Parkinson's disease pathogenesis. Experimental neurology 79 24907399
2006 LRRK2: a common pathway for parkinsonism, pathogenesis and prevention? Trends in molecular medicine 77 16406842
2020 LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes. The EMBO journal 76 32853409
2017 Leucine-Rich Repeat Kinase (LRRK2) Genetics and Parkinson's Disease. Advances in neurobiology 72 28353276
2015 Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers. PloS one 70 26177462
2015 LRRK2 dephosphorylation increases its ubiquitination. The Biochemical journal 60 25939886
2021 LRRK2 recruitment, activity, and function in organelles. The FEBS journal 59 34196120
2012 Mechanisms of LRRK2-mediated neurodegeneration. Current neurology and neuroscience reports 57 22441981
2021 Parkinson's disease and mitophagy: an emerging role for LRRK2. Biochemical Society transactions 56 33769432
2020 The Emerging Functions of LRRK2 and Rab GTPases in the Endolysosomal System. Frontiers in neuroscience 56 32256311
2017 Structural interface between LRRK2 and 14-3-3 protein. The Biochemical journal 55 28202711
2009 LRRK2 and neurodegeneration. Acta neuropathologica 55 19142648
2020 Endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity. The Biochemical journal 53 33135724
2007 LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8. Neurology 52 17804834
2020 LRRK2 Phosphorylation, More Than an Epiphenomenon. Frontiers in neuroscience 51 32612495
2017 The LRRK2-macroautophagy axis and its relevance to Parkinson's disease. Biochemical Society transactions 51 28202669
2021 Impact of Type II LRRK2 inhibitors on signaling and mitophagy. The Biochemical journal 50 34515301
2017 Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity. Advances in neurobiology 50 28353279
2017 LRRK2 and Autophagy. Advances in neurobiology 49 28353280
2012 The GTPase function of LRRK2. Biochemical Society transactions 48 22988866
2009 LRRK2 in Parkinson's disease: biochemical functions. The FEBS journal 48 19804416
2017 LRRK2 and the Immune System. Advances in neurobiology 47 28353282
2015 LRRK2 autophosphorylation enhances its GTPase activity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 46 26396237
2013 Contribution of GTPase activity to LRRK2-associated Parkinson disease. Small GTPases 45 24025585
2022 Lysosomal positioning regulates Rab10 phosphorylation at LRRK2+ lysosomes. Proceedings of the National Academy of Sciences of the United States of America 44 36256825
2019 Autophagy and LRRK2 in the Aging Brain. Frontiers in neuroscience 44 31920513
2018 The role of LRRK2 in cell signalling. Biochemical Society transactions 42 30578345
2007 Mutations in LRRK2 as a cause of Parkinson's disease. Neuro-Signals 42 18097165
2006 Recurrent LRRK2 (Park8) mutations in early-onset Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 42 16758483
2021 LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade. Life science alliance 41 33727250
2025 A STING-CASM-GABARAP pathway activates LRRK2 at lysosomes. The Journal of cell biology 40 39812709
2018 LRRK2 and Rab GTPases. Biochemical Society transactions 39 30467121
2015 LRRK2 Promotes Tau Accumulation, Aggregation and Release. Molecular neurobiology 39 26014385
2012 Phosphorylation of LRRK2: from kinase to substrate. Biochemical Society transactions 39 22988873
2016 LRRK2 variation and dementia with Lewy bodies. Parkinsonism & related disorders 38 27521182
2020 Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations. eLife 37 33006315
2020 Selective Inhibitors of G2019S-LRRK2 Kinase Activity. Journal of medicinal chemistry 37 33197196
2022 Structural basis for Parkinson's disease-linked LRRK2's binding to microtubules. Nature structural & molecular biology 36 36510024
2022 Directing LRRK2 to membranes of the endolysosomal pathway triggers RAB phosphorylation and JIP4 recruitment. Neurobiology of disease 35 35580815
2020 G2019S-LRRK2 mutation enhances MPTP-linked Parkinsonism in mice. Human molecular genetics 35 31813996
2019 LRRK2 in Infection: Friend or Foe? ACS infectious diseases 35 30915830
2023 Rab12 is a regulator of LRRK2 and its activation by damaged lysosomes. eLife 33 37874617
2020 Leucine-rich repeat kinase-2 (LRRK2) modulates microglial phenotype and dopaminergic neurodegeneration. Neurobiology of aging 33 32247534
2017 Mechanisms of Mutant LRRK2 Neurodegeneration. Advances in neurobiology 33 28353287
2019 Rab GTPases as Physiological Substrates of LRRK2 Kinase. Experimental neurobiology 32 31138985
2022 LRRK2 as a target for modulating immune system responses. Neurobiology of disease 31 35427743
2018 The LRRK2 signalling system. Cell and tissue research 31 29308544
2018 The G2019S mutation in LRRK2 imparts resiliency to kinase inhibition. Experimental neurology 31 30048714
2017 Cross-talk between LRRK2 and PKA: implication for Parkinson's disease? Biochemical Society transactions 30 28202680
2015 Function and dysfunction of leucine-rich repeat kinase 2 (LRRK2): Parkinson's disease and beyond. BMB reports 30 25703537
2015 Structural Characterization of LRRK2 Inhibitors. Journal of medicinal chemistry 30 25897865
2012 Mouse models for LRRK2 Parkinson's disease. Parkinsonism & related disorders 29 22166430
2020 Mitochondrial Mechanisms of LRRK2 G2019S Penetrance. Frontiers in neurology 28 32982917
2017 Small-Molecule Inhibitors of LRRK2. Advances in neurobiology 28 28353288
2012 LRRK2 and vesicle trafficking. Biochemical Society transactions 28 22988875
2015 LRRK2 mutations and neurotoxicant susceptibility. Experimental biology and medicine (Maywood, N.J.) 27 25888648
2021 Hyperactive LRRK2 kinase impairs the trafficking of axonal autophagosomes. Autophagy 26 34110246
2021 LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation. Brain : a journal of neurology 25 33876242
2012 A link between LRRK2, autophagy and NAADP-mediated endolysosomal calcium signalling. Biochemical Society transactions 25 22988879
2010 Expression of leucine-rich-repeat-kinase 2 (LRRK2) during embryonic development. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 24 20403420
2023 LRRK2 aggravates kidney injury through promoting MFN2 degradation and abnormal mitochondrial integrity. Redox biology 23 37633049
2021 LRRK2 correlates with macrophage infiltration in pan-cancer. Genomics 23 34929286
2019 Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype. Journal of neuroinflammation 23 31174552
2018 The role of LRRK2 in cytoskeletal dynamics. Biochemical Society transactions 23 30467120
2018 Physiological and pathological functions of LRRK2: implications from substrate proteins. Neuronal signaling 23 32714591
2014 Interaction of LRRK2 with kinase and GTPase signaling cascades. Frontiers in molecular neuroscience 23 25071441
2011 Role of LRRK2 kinase dysfunction in Parkinson disease. Expert reviews in molecular medicine 23 21676337
2017 LRRK2 Phosphorylation. Advances in neurobiology 21 28353278

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