Abstract
Progressive degeneration of dopaminergic neurons, immune activation, and α-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 α-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 α-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 [3H]raclopride, [3H]DTBZ, [3H]GBR12935, [3H]PK11195, and [3H]UCB-J to measure binding at D2/3 receptors, vesicular monoamine transporter 2, dopamine transporters, mitochondrial translocator protein, and SV2A, respectively. rAAV-α-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, α-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.
Highlights
No difference was found in the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) among the groups, we observed a significant increase in the DOPAC/dopamine ratio, a measure of dopamine turnover, in the ASYN animals compared to the green fluorescent protein (GFP) animals
We showed that the overexpression of human rAAV2/6-ASYN led to motor deficits, induced changes in the pre- and postsynaptic dopaminergic system, and promoted neuroinflammation measured by translocator protein (TSPO) expression in the striatum and SN
We demonstrate that unilateral overexpression of human ASYN in the nigrostriatal system leads to motor deficits and reduced tyrosine hydroxylase (TH) mRNA in the SN, decreased levels of dopamine in the striatum and mild, yet significant, compensatory increased expression of striatal dopamine 2/3 (D2/3) receptors
Summary
Parkinson’s disease (PD) is a chronic neurodegenerative disease with symptoms of bradykinesia, rigidity and tremor, among others. It is characterized by progressive degeneration of the dopaminergic neurons in the substantia nigra (SN) and the presence of α-synuclein (ASYN) containing Lewy bodies [1]. ASYN is a 140 amino acid protein localized in the synapse, where it associates with vesicles. ASYN is present as a soluble unfolded monomer or helically folded tetramer [2,3], but during PD, ASYN aggregates and forms intraneuronal Lewy bodies and neurites [4,5,6].
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