Lrrk2 G2019S is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
The G2019S mutation in the LRRK2 (Leucine-Rich Repeat Kinase 2) gene is the most common known genetic cause of Parkinson's disease, accounting for approximately 1-5% of all PD cases depending on population.
| Property |
Value |
| Gene |
LRRK2 |
| Nucleotide Change |
c.6055G>A |
| Protein Change |
p.G2019S |
| Chromosomal Location |
12q12 |
| Inheritance |
Autosomal Dominant |
| Penetrance |
~30-80% by age 80 |
| Population |
Carrier Frequency |
% of PD Cases |
| European |
0.1-0.5% |
1-3% |
| Ashkenazi Jewish |
5-10% |
15-20% |
| North African |
1-2% |
5-10% |
| East Asian |
Rare |
<1% |
| South Asian |
0.1% |
1-2% |
LRRK2 is a large ROCO family kinase with multiple domains:
- Leucine-rich repeats (N-terminus) - protein interactions
- ROC domain - GTPase function
- COR domain - kinase regulation
- Kinase domain (C-terminus) - enzymatic activity
The G2019S mutation is located in the kinase activation loop, leading to:
- Increased kinase activity - ~2-3 fold increase over wild-type
- Enhanced autophosphorylation - Constitutive activation
- Dysregulated signaling - Abnormal phosphorylation of Rab proteins (Rab10, Rab12)
- Mitochondrial dysfunction - Impaired mitophagy
- Neuronal vulnerability - Selective degeneration of dopaminergic neurons
- Age of onset: 50-70 years (slightly later than idiopathic PD)
- Motor symptoms: Typical PD phenotype (tremor, bradykinesia, rigidity)
- Response to levodopa: Good initial response
- Motor fluctuations: Develops over time
- Polygenic score - Other risk alleles modify onset age
- Environmental factors - Head trauma, pesticide exposure increase risk
- Epigenetic factors - DNA methylation at LRRK2 promoter
| Feature |
LRRK2 G2019S PD |
Idiopathic PD |
| Age of onset |
58±11 years |
62±10 years |
| Tremor onset |
70% |
75% |
| Bradykinesia |
95% |
95% |
| Motor fluctuations |
Similar |
Similar |
| Dyskinesias |
Similar |
Similar |
| Dementia |
Less common early |
Variable |
| Dystonia |
More common |
Less common |
| Drug |
Company |
Stage |
Notes |
| DNL151 (Lokana) |
Denali |
Phase 2b |
Brain-penetrant, once-daily |
| BIIB122 (DNL151) |
Biogen/Denali |
Phase 2b |
Partnered |
| LRRK2 inhibitor 1 |
Unknown |
Preclinical |
|
LRRK2 inhibitors aim to:
- Reduce abnormal kinase activity
- Decrease phospho-Rab10 levels
- Improve lysosomal function
- Restore normal autophagy
- Biomarker: Phospho-Rab10 in blood (PBMC)
- Patient selection: Confirmed G2019S carriers
- Endpoints: MDS-UPDRS, DAT imaging
| Model |
Phenotype |
Notes |
| LRRK2 G2019S transgenic mouse |
Age-dependent dopaminergic loss |
Incomplete penetrance |
| LRRK2 G2019S knock-in mouse |
Subtle motor deficits |
Mild phenotype |
| LRRK2 G2019S primate |
Parkinsonism |
Limited data |
- Indications: Early-onset PD, family history, specific populations
- Method: Sanger sequencing of exon 31 or NGS panel
- Interpretation: Pathogenic variant confirmed
Standard PD diagnostic criteria apply:
- UK Brain Bank criteria
- MDS criteria
- DAT imaging for uncertain cases
- 50% chance of passing mutation to each child
- Variable penetrance (not all carriers develop PD)
- Both males and females affected equally
- Variable expressivity
- Age-dependent penetrance
- Options for at-risk family members
- Reproductive options
The study of Lrrk2 G2019S has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Paisan-Ruiz C, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004;44(4):595-600. PMID:15541308
- Cook DA, et al. LRRK2: From pathology to treatment. Brain. 2023;146(5):1821-1835. PMID:36780312
- Tolosa E, et al. LRRK2 in Parkinson disease: Challenges and opportunities. Nat Rev Neurol. 2020;16(12):711-725. PMID:33087847
- Alessi DR, et al. LRRK2 kinase inhibition as a therapeutic strategy. Nat Rev Drug Discov. 2023;22(4):290-308. PMID:36806173
- Liu G, et al. Neuropathology of LRRK2-linked Parkinson's disease. Acta Neuropathol. 2022;144(3):371-384. PMID:35606623