Genetic Basis of Parkinson Disease
Parkinson disease results from progressive loss of dopaminergic neurons in the substantia nigra, leading to characteristic motor symptoms including tremor, rigidity, and bradykinesia. While most cases are sporadic, genetic studies have identified numerous loci associated with familial and sporadic disease risk.
SNCA (Alpha Synuclein)
Point mutations (A53T, A30P, E46K) and gene multiplications cause autosomal dominant Parkinson disease. Alpha synuclein aggregation into Lewy bodies is a pathological hallmark.
LRRK2
The G2019S mutation is the most common genetic cause of Parkinson disease. Increased LRRK2 kinase activity is implicated in both familial and sporadic disease.
PARK2, PINK1, DJ1
Recessive mutations cause early onset parkinsonism. These genes function in mitochondrial quality control and mitophagy pathways.
GBA
Heterozygous GBA mutations are the most common genetic risk factor for sporadic Parkinson disease, increasing risk approximately fivefold.
Model Types for Parkinson Disease Research
Alpha Synuclein Models
- SNCA Point Mutation Knockin (A53T, A30P, E46K)
- SNCA Overexpression Transgenic
- SNCA Knockout
- Conditional SNCA Models
LRRK2 Models
- LRRK2 G2019S Knockin
- LRRK2 Kinase Dead Knockin
- LRRK2 Knockout
- LRRK2 R1441C/G Knockin
Mitochondrial Pathway
- Parkin (Park2) Knockout
- PINK1 Knockout
- DJ1 (Park7) Knockout
GBA Models
- GBA Point Mutation Knockin (N370S, L444P)
- Conditional GBA Knockout
Cell Type Specific Approaches
Parkinson disease selectively affects specific neuronal populations. Conditional approaches target relevant cell types.
Dopaminergic Neuron Targeting
DAT Cre or TH Cre
Catecholaminergic neurons; DAT Cre more restricted to dopaminergic neurons
Regional Specificity
En1 Cre or Pitx3 Cre
Midbrain dopaminergic neurons from early development
Temporal Control
DAT CreERT2
Gene manipulation in adult dopaminergic neurons, avoiding developmental compensation
Phenotyping Parkinson Disease Models
Motor Assessment
Open Field
Spontaneous locomotor activity, rearing, and movement patterns
Rotarod
Motor coordination and balance with accelerating protocols
Pole Test
Bradykinesia assessment; time to descend correlates with dopaminergic function
Gait Analysis
Stride length, cadence, and coordination; automated systems available
Cylinder Test
Forelimb asymmetry in unilateral lesion models
Neuropathology Endpoints
- Dopaminergic neuron counts: Stereological quantification of TH positive neurons in substantia nigra
- Striatal dopamine: HPLC measurement of dopamine and metabolites
- Synuclein pathology: Phospho synuclein (Ser129), aggregated synuclein, Lewy body like inclusions
- Neuroinflammation: Microglial activation (Iba1), astrogliosis (GFAP), and inflammatory markers
Selected Publications in Parkinson Disease Research
Recent publications demonstrate the utility of genetically engineered mouse models in Parkinson disease research:
Lunn MO et al. (2025).
Variants in Lrrk2 and Snca deficiency do not alter the course of primary encephalitis due to neurotropic reovirus T3D in newborn mice. ↗PLoS One 20(5): e0318685
Clausen BE et al. (1999).
Conditional gene targeting in macrophages and granulocytes using LysMcre mice. ↗Transgenic Research 8(4): 265-277
What Researchers Say
“ingenious Targeting Laboratory is highly recommended for generating custom animal models. Past 2 years, we have made 2 conditional knockout mouse lines. All processes of each project were scientifically and professionally handled. Their scientific consulting to initiate the project was superb compared to other companies, and transparency of the project progress reported by project managers was excellent. Their excellency and dedication to meet our needs in a timely manner are invaluable to continuation of our research progress.”
— Hyekyung Plumley, PhD
Warren Center for Neuroscience Drug Discovery
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