α-Synuclein Overexpression Increases Dopamine D2/3 Receptor Binding and Immune Activation in a Model of Early Parkinson's Disease

Progressive degeneration of dopaminergic neurons, immune activation, and alpha-synuclein pathology characterize Parkinson's disease (PD). We previously reported that unilateral intranigral injection of recombinant adeno-associated viral (rAAV) vectors encoding wild-type human alpha-synuclein produced a rat model of early PD with dopamine terminal dysfunction. Here we tested the hypothesis that decreases in dopamine result in increased postsynaptic dopamine D2/D3 receptor expression, neuroinflammation, and reduced synaptic vesicle glycoprotein 2A (SV2A) density. Rats were injected with rAAV encoding alpha-synuclein or green fluorescent protein and subjected to non-pharmacological motor tests, before euthanization at 12 weeks post-injection. We performed: (1) in situ hybridization of nigral tyrosine hydroxylase mRNA, (2) HPLC of striatal dopamine content, and (3) autoradiography with [H-3]raclopride, [H-3]DTBZ, [H-3]GBR12935, [H-3]PK11195, and [H-3]UCB-J to measure binding at D2/3 receptors, vesicular monoamine transporter 2, dopamine transporters, mitochondrial translocator protein, and SV2A, respectively. rAAV-alpha-synuclein induced motor asymmetry and reduced tyrosine hydroxylase mRNA and dopamine content in ipsilateral brain regions. This was paralleled by elevated ipsilateral postsynaptic dopamine D2/3 receptor expression and immune activation, with no changes to synaptic SV2A density. In conclusion, alpha-synuclein overexpression results in dopaminergic degeneration that induced compensatory increases in D2/3 binding and immune activation, recapitulating many of the pathological characteristics of PD.

Automated summary

The overexpression of alpha-synuclein leads to dopaminergic degeneration, resulting in compensatory increases in D2/3 receptor binding and immune activation, recapitulating many of the pathological characteristics of Parkinson's disease.