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50 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
LRRK2
leucine rich repeat kinase 2
Chromosome 12 Β· 12q12
NCBI Gene: 120892Ensembl: ENSG00000188906.18HGNC: HGNC:18618UniProt: Q17RV3
1,107PubMed Papers
21Diseases
0Drugs
10Pathogenic Variants
FUNCTIONAL ROLE
Hub GeneKinase
RESEARCH IMPACT
Highly StudiedTrending
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
GO:0005615kinase activitysyntaxin-1 bindingnegative regulation of GTPase activityHereditary late-onset Parkinson diseaseParkinson diseaseYoung adult-onset Parkinsonismlate-onset Parkinson disease
✦AI Summary

LRRK2 is a serine/threonine-protein kinase that functions as a critical regulator of multiple cellular processes implicated in Parkinson's disease (PD) pathogenesis 1. The kinase phosphorylates a broad range of proteins involved in neuronal plasticity, innate immunity, autophagy, and vesicle trafficking 2. A primary mechanism involves LRRK2's regulation of RAB GTPases; the kinase phosphorylates RAB3, RAB5, RAB8, RAB10, and RAB29, modulating their activity and governing endolysosomal dynamics and ciliogenesis 3. LRRK2 is dynamically recruited to stressed or damaged lysosomes through GABARAP-CASM pathway interactions, where it phosphorylates RAB substrates to promote lysosomal content release and suppress pathological enlargement 4. Additionally, LRRK2 suppresses lysosomal degradative activity through MiT-TFE transcription factor inhibition, with hyperactive disease mutants exacerbating this suppression 5. Mutations in LRRK2 represent the most common genetic cause of familial PD and are implicated in sporadic disease; LRRK2-PD exhibits variable pathology with inconsistent Lewy body pathology but marked Alzheimer-type changes 1. Beyond PD, LRRK2 dysfunction contributes to acute kidney injury through MFN2-dependent mitochondrial fragmentation 6. Emerging LRRK2-targeted therapies aim to normalize kinase activity and restore lysosomal homeostasis.

Sources cited
1
LRRK2 variants implicated in familial and sporadic PD; LRRK2-PD has variable pathology with inconsistent Lewy bodies and marked Alzheimer pathology
PMID: 37021623
2
LRRK2 is the most common cause of familial PD; recent advances in understanding LRRK2's functions in endolysosomal system and regulation of Rab GTPases
PMID: 33526455
3
LRRK2 kinase activity dynamically regulated by recruitment to endolysosomal membranes; Rab family GTPases act as both activators and substrates; LRRK2 recruited to damaged lysosomes via GABARAP-CASM pathway
PMID: 39983584
4
LRRK2 phosphorylates RAB8a and RAB10; LRRK2-dependent phosphorylation results in RAB inactivation; opposing effects on lysosomal pH, Golgi organization, and pathological protein accumulation
PMID: 38307024
5
LRRK2 suppresses lysosomal degradative activity through MiT-TFE transcription factor inhibition; G2019S mutant exacerbates suppression
PMID: 37487100
6
LRRK2 downregulated in acute kidney injury; promotes MFN2 degradation and mitochondrial fragmentation; LRRK2 inhibitors attenuate AKI and fibrosis
PMID: 37633049
Disease Associationsβ“˜21
Hereditary late-onset Parkinson diseaseOpen Targets
0.83Strong
Parkinson diseaseOpen Targets
0.77Strong
Young adult-onset ParkinsonismOpen Targets
0.55Moderate
late-onset Parkinson diseaseOpen Targets
0.45Moderate
neurodegenerative diseaseOpen Targets
0.44Moderate
genetic disorderOpen Targets
0.42Moderate
leprosyOpen Targets
0.38Weak
Parkinson disease, dominantOpen Targets
0.37Weak
Alzheimer diseaseOpen Targets
0.36Weak
Abruptio PlacentaeOpen Targets
0.34Weak
multiple sclerosisOpen Targets
0.34Weak
lysosomal storage diseaseOpen Targets
0.34Weak
Abnormal pulmonary interstitial morphologyOpen Targets
0.33Weak
Klippel-Feil syndrome 1, autosomal dominantOpen Targets
0.33Weak
Spinocerebellar atrophyOpen Targets
0.33Weak
neuroinflammatory disorderOpen Targets
0.31Weak
Crohn's diseaseOpen Targets
0.30Weak
respiratory failureOpen Targets
0.28Weak
ulcerative colitisOpen Targets
0.26Weak
sclerosing cholangitisOpen Targets
0.23Weak
Parkinson disease 8UniProt
Pathogenic Variants10
NM_198578.4(LRRK2):c.6055G>A (p.Gly2019Ser)Pathogenic
Autosomal dominant Parkinson disease 8|not provided|Inborn genetic diseases|Young-onset Parkinson disease|Parkinson disease, late-onset|LRRK2-related disorder|Parkinson disease
β˜…β˜…β˜†β˜†2026β†’ Residue 2019
NM_198578.4(LRRK2):c.4321C>T (p.Arg1441Cys)Pathogenic
Autosomal dominant Parkinson disease 8|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 1441
NM_198578.4(LRRK2):c.4321C>G (p.Arg1441Gly)Pathogenic
Autosomal dominant Parkinson disease 8|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 1441
NM_198578.4(LRRK2):c.4322G>A (p.Arg1441His)Pathogenic
Autosomal dominant Parkinson disease 8
β˜…β˜…β˜†β˜†2024β†’ Residue 1441
NM_198578.4(LRRK2):c.4318G>C (p.Ala1440Pro)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2024β†’ Residue 1440
NM_198578.4(LRRK2):c.6059T>C (p.Ile2020Thr)Pathogenic
Autosomal dominant Parkinson disease 8|not provided
β˜…β˜†β˜†β˜†2020β†’ Residue 2020
NM_198578.4(LRRK2):c.4321C>A (p.Arg1441Ser)Likely pathogenic
Parkinson disease, late-onset|Autosomal dominant Parkinson disease 8
β˜…β˜†β˜†β˜†2018β†’ Residue 1441
NM_198578.4(LRRK2):c.4969C>T (p.Gln1657Ter)Pathogenic
Interstitial pulmonary disease
β˜†β˜†β˜†β˜†2021β†’ Residue 1657
NM_198578.4(LRRK2):c.5096A>G (p.Tyr1699Cys)Pathogenic
Autosomal dominant Parkinson disease 8
β˜†β˜†β˜†β˜†2005β†’ Residue 1699
NM_198578.4(LRRK2):c.3364A>G (p.Ile1122Val)Pathogenic
Autosomal dominant Parkinson disease 8
β˜†β˜†β˜†β˜†2004β†’ Residue 1122
View on ClinVar β†—
Related Genes
HSPA8Protein interaction100%HSP90AA1Protein interaction100%HSP90AB1Protein interaction100%HSPA4Protein interaction100%DVL1Protein interaction100%RAB29Protein interaction100%
Tissue Expression6 tissues
Lung
100%
Bone Marrow
23%
Ovary
21%
Heart
11%
Brain
10%
Liver
7%
Gene Interaction Network
Click a node to explore
LRRK2HSPA8HSP90AA1HSP90AB1HSPA4DVL1RAB29
PROTEIN STRUCTURE
Preparing viewer…
PDB5MY9 Β· 1.33 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.78LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.69 [0.61–0.78]
RankingsWhere LRRK2 stands among ~20K protein-coding genes
  • #138of 20,598
    Most Researched1,107 Β· top 1%
  • #2,813of 5,498
    Most Pathogenic Variants10
  • #6,355of 17,882
    Most Constrained (LOEUF)0.78
Genes detectedLRRK2
Sources retrieved50 papers
Response timeβ€”
πŸ“„ Sources
50β–Ό
1
LRRK2 and Parkinson's disease: from genetics to targeted therapy.
PMID: 37021623
Ann Clin Transl Neurol Β· 2023
1.00
2
The Cell Biology of LRRK2 in Parkinson's Disease.
PMID: 33526455
Mol Cell Biol Β· 2021
0.90
3
LRRK2 and the Immune System.
PMID: 28353282
Adv Neurobiol Β· 2017
0.82
4
LRRK2, lysosome damage, and Parkinson's disease.
PMID: 39983584
Curr Opin Cell Biol Β· 2025
0.80
5
LRRK2 Structure-Based Activation Mechanism and Pathogenesis.
PMID: 37189360
Biomolecules Β· 2023
0.80