The AAV-LRRK2 gene delivery model uses viral vectors to deliver wild-type or mutant LRRK2 to specific brain regions, providing a flexible system for studying LRRK2 pathogenesis and therapeutic intervention.
| Serotype |
CNS Tropism |
Efficiency |
Clinical Relevance |
| AAV9 |
Neurons, astrocytes |
High |
Clinical trials |
| AAV2 |
Neurons |
Moderate |
Historical |
| AAV1 |
Neurons |
Moderate |
Gene therapy |
| AAV-PHP.B |
Pan-neuronal |
Very high |
Research |
| AAV-DJ |
Neurons |
High |
Research |
- CMV: Strong, constitutive expression
- Synapsin: Neuron-specific expression
- GFAP: Astrocyte-specific expression
- MeCP2: Neuronal activity-dependent
- Overexpression of normal LRRK2 protein
- Used to study gain-of-function mechanisms
- Typical expression: 2-5x endogenous levels
| Mutation |
Effect |
Frequency in PD |
Model Use |
| G2019S |
Kinase activation (↑ 2-3x) |
~5% familial |
Most common |
| R1441C/G/H |
GTPase alteration |
~3% familial |
GTPase domain |
| N1437H |
GTPase alteration |
Rare |
GTPase domain |
| K1998E |
GTPase alteration |
Rare |
GTPase domain |
The G2019S mutation increases LRRK2 kinase activity 2-3 fold:
- Substrate phosphorylation: Enhanced phosphorylation of Rab proteins (Rab8A, Rab10, Rab12)
- Lysosomal dysfunction: Altered lysosomal trafficking and function
- Autophagy impairment: Dysregulated autophagic flux
- Neurite pathology: Reduced neurite length and branching
- Altered synaptic vesicle dynamics
- Impaired dopamine release and reuptake
- Synaptic α-synuclein accumulation
The model enables testing of:
- LRRK2 kinase inhibitors: DNL151, DLB-45365
- Antisense oligonucleotides: BIIB100
- Autophagy enhancers: Trehalose, rapamycin
- Neuroprotective agents: CoQ10, nicotinamide
- Rab pathway: Identify downstream effectors of LRRK2 hyperactivation
- Cell-type specificity: Understand which neurons are most vulnerable
- Interaction with α-synuclein: Synergistic pathology with SNCA
¶ Advantages and Limitations
- Temporal control: Expression can be induced at specific times
- Spatial control: Targeting to specific brain regions
- Dose-titratable: Variable viral doses control expression level
- No developmental effects: Adult-onset expression
- Compatible with other models: Can combine with transgenic or toxin models
- Acute overexpression: Not a chronic developmental model
- Non-physiological levels: Expression may exceed endogenous levels
- Immune response: AAV capsid immunity in some subjects
- Variable transduction: Batch-to-batch and animal-to-animal variation
¶ Standard Protocol
- Stereotactic injection: AAV into striatum or substantia nigra
- Expression timeline: Peak expression at 2-4 weeks
- Analysis window: 4-12 weeks post-injection
- Behavioral testing: Rotarod, cylinder, gait analysis
- AAV-GFP or AAV-lacZ control vector
- Isogenic wild-type LRRK2 control
- Uninjected contralateral hemisphere
- Daher et al., 2014 - AAV-mediated LRRK2 overexpression in mice
- Volpicelli-Daley et al., 2016 - LRRK2 and α-synuclein interaction
- Steger et al., 2016 - LRRK2 kinase activity in vivo
- Blandini et al., 2020 - AAV-LRRK2 models and therapeutic screening
- Javed et al., 2019 - LRRK2-targeted therapies in preclinical models