ABSTRACT:
We used in vivo amperometry to monitor changes in synaptic dopamine (DA) release in the striatum induced by overexpression of human wild-type α-synuclein in nigral DA neurons, induced by injection of an adeno-associated virus type 6 (AAV6)–α-synuclein vector unilaterally into the substantia nigra in adult rats. Impairments in DA release evolved in parallel with the development of degenerative changes in the nigro-striatal axons and terminals. The earliest change, seen 10 d after vector injection, was a marked, ≈50%, reduction in DA reuptake, consistent with an early dysfunction of the DA transporter that developed before any overt signs of axonal damage. At 3 wk, when the first signs of axonal damage were observed, the amount of DA released after a KCl pulse was reduced by 70–80%, and peak DA concentration was delayed, indicating an impaired release mechanism. At later time points, 8–16 wk, overall striatal innervation density was reduced by 60–80% and accompanied by abundant signs of axonal damage in the form of α-synuclein aggregates, axonal swellings, and dystrophic axonal profiles. At this stage DA release and reuptake were profoundly reduced, by 80–90%. The early changes in synaptic DA release induced by overexpression of human α-synuclein support the idea that early predegenerative changes in the handling of DA may initiate, and drive, a progressive degenerative process that hits the axons and terminals first. Synaptic dysfunction and axonopathy would thus be the hallmark of presymptomatic and early-stage Parkinson's disease, followed by neuronal degeneration and cell loss, characteristic of more advanced stages of the disease.
Vidyadhara started with a short introduction that included some history about Parkinson's Disease (PD) and went on to the existing animal models and their limitation in addressing the core aspect of the disease (i.e. progressive neurodegeneration). He introduced the major molecule targeted in the model proposed in the paper, alpha-synuclein, and how it has been hypothesized in the disease mechanism.
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The paper tries to validate the alpha-synuclein over-expression model of PD, by trying to prove that progressive over-expression of alpha-synuclein evoked locally in nigro-striatal axons can cause decrease in DA re-uptake as well as its release.
Some salient queries were:
- Is alpha-synuclein over-expression primarily compensatory or pathological?
- Role of pre-synaptic DA receptors in regulating DA re-uptake? how is it influenced by alpha-synuclein?