The [LRRK2](/entities/lrrk2) (Leucine-Rich Repeat Kinase 2) gene encodes a large multi-domain protein with kinase activity. Pathogenic variants in LRRK2 are among the most common genetic causes of familial Parkinson's disease.
Overview
| Property | Value | [@investigating] |----------|-------| [@evidence] | Gene Symbol | LRRK2 | [@genotypeassociated] | Full Name | Leucine-Rich Repeat Kinase 2 | | Chromosomal Location | 12q12 | | NCBI Gene ID | 120892 | | OMIM | [609007](https://www.omim.org/entry/609007) | | Ensembl ID | ENSG00000188906 | | UniProt ID | [Q5S007](https://www.uniprot.org/uniprotkb/Q5S007) | | Inheritance | Autosomal Dominant | | Protein Domains | ROC (Ras of complex), COR, Kinase, LRR, ANK, WD40 |
Function
LRRK2 is a large cytosolic protein (2527 amino acids) with multiple functional domains:
Kinase domain: Phosphorylates target proteins (including itself through autophosphorylation)
ROC domain: GTPase activity, regulates protein interactions
COR domain: Mediates dimerization
LRR domain: Protein-protein interactions
WD40 repeat: Scaffold for protein complexes
Normal Functions
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LRRK2 Gene Variants and Mutations
The [LRRK2](/entities/lrrk2) (Leucine-Rich Repeat Kinase 2) gene encodes a large multi-domain protein with kinase activity. Pathogenic variants in LRRK2 are among the most common genetic causes of familial Parkinson's disease.
Overview
| Property | Value | [@investigating] |----------|-------| [@evidence] | Gene Symbol | LRRK2 | [@genotypeassociated] | Full Name | Leucine-Rich Repeat Kinase 2 | | Chromosomal Location | 12q12 | | NCBI Gene ID | 120892 | | OMIM | [609007](https://www.omim.org/entry/609007) | | Ensembl ID | ENSG00000188906 | | UniProt ID | [Q5S007](https://www.uniprot.org/uniprotkb/Q5S007) | | Inheritance | Autosomal Dominant | | Protein Domains | ROC (Ras of complex), COR, Kinase, LRR, ANK, WD40 |
Function
LRRK2 is a large cytosolic protein (2527 amino acids) with multiple functional domains:
Kinase domain: Phosphorylates target proteins (including itself through autophosphorylation)
ROC domain: GTPase activity, regulates protein interactions
COR domain: Mediates dimerization
LRR domain: Protein-protein interactions
WD40 repeat: Scaffold for protein complexes
Normal Functions
Neuronal signaling: Regulates various signaling pathways in [neurons](/entities/neurons)
Protein sorting: Controls vesicular trafficking through Rab GTPase interactions
Mitochondrial function: Associates with mitochondrial outer membrane
Synaptic plasticity: Involved in dopamine receptor signaling
Parkinson's Disease (PD) - LRRK2 is the most common genetic cause of late-onset familial PD, accounting for 5-10% of familial cases and 1-5% of sporadic cases.
Key Pathogenic Mutations
| Mutation | Domain | Effect | Prevalence | |----------|--------|--------|------------| | G2019S | Kinase | Increased kinase activity | Most common (~5% familial PD) | | R1441C | ROC | Impaired GTPase activity | Second most common | | R1441G | ROC | Impaired GTPase activity | Common in Basque population | | R1441H | ROC | Impaired GTPase activity | Variable penetrance | | Y1699C | COR | Altered function | Rare | | G2385R | WD40 | Risk variant | Asian populations | | R1628P | WD40 | Risk variant | Asian populations |
Geographic Distribution
G2019S: Common in European and North African populations (up to 30% of familial PD in some populations)
R1441G: Highly prevalent in Basque population (up to 50% of familial PD)
G2385R: Risk factor in East Asian populations
Penetrance
The penetrance of LRRK2 mutations is age-dependent and incomplete:
G2019S: ~70% by age 80
R1441C/G: ~30-50% by age 80
Variable depending on specific mutation and population
Pathogenic Mechanisms
Kinase hyperactivity: G2019S increases kinase activity, leading to enhanced downstream signaling
GTPase dysfunction: R1441 mutations impair ROC domain function
Mitochondrial dysfunction: Altered mitochondrial quality control
Dysregulated autophagy: Impaired lysosomal and autophagic clearance
Neuroinflammation: Activation of [microglia](/cell-types/microglia-neuroinflammation) and inflammatory pathways
Expression
LRRK2 is widely expressed in the central and peripheral nervous system:
Substantia nigra - Dopaminergic neurons (vulnerable in PD)
[Cortex](/brain-regions/cortex) - Especially frontal and temporal regions
Striatum - Major target of dopaminergic input
[Hippocampus](/brain-regions/hippocampus) - Involved in learning and memory
Peripheral tissues - Kidneys, lungs, immune cells
Expression is also prominent in:
Kidney and lung tissue
Immune cells (monocytes, macrophages)
Therapeutic Implications
Current Strategies
LRRK2 kinase inhibitors: Small molecule inhibitors (e.g., DNL151, BIIB122)
Antisense oligonucleotides: siRNA approaches to reduce LRRK2 expression
Protein-protein interaction inhibitors: Targeting ROC-COR or LRR domain interactions
Clinical Trials
Multiple LRRK2 kinase inhibitors in clinical trials for PD
[Dopamine Signaling in PD](/mechanisms/dopamine-signaling-parkinsons) - Dopaminergic dysfunction
Key Publications
[Paisán-Ruíz et al., Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease (2005)](https://doi.org/10.1016/j.neuron.2004.11.069)
[Zimprich et al., Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology (2004)](https://doi.org/10.1016/j.neuron.2004.11.005)
[Di Fonzo et al., A common missense variant in LRRK2 is a major risk factor for Parkinson's disease (2005)](https://doi.org/10.1016/j.cell.2005.10.035)
[Cookson, The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease (2010)](https://doi.org/10.1038/nrn2786)
This section highlights recent publications relevant to this disease.
[Convergent molecular pathways to inherited Parkinson's disease.](https://pubmed.ncbi.nlm.nih.gov/41719940/) (2026 Apr) - Current opinion in cell biology
[Investigating the Genetic Relationship Between Vitamin B12 Metabolism and Parkinson Disease.](https://pubmed.ncbi.nlm.nih.gov/41710648/) (2026 Apr) - Neurology. Genetics
[No evidence for the LRRK2 p.L1795F variant in a Southern Italian cohort with Parkinson's disease.](https://pubmed.ncbi.nlm.nih.gov/41500415/) (2026 Mar 20) - Gene
[Genotype-associated outcomes after deep brain stimulation in Parkinson's disease: a systematic review, meta-analysis and epigenetic implications.](https://pubmed.ncbi.nlm.nih.gov/41823280/) (2026 Mar 13) - Neurologia i neurochirurgia polska
[LRRK2 kinase mediates increased GCase activity in microglia in response to IFNγ-induced proinflammatory stimulation.](https://pubmed.ncbi.nlm.nih.gov/41786767/) (2026 Mar 6) - NPJ Parkinson's disease