Times change, observation improves, reality changes.

[Gioc]

”Abstract:

Parkinson’s disease is the second most common neurodegenerative disease and yet the early pathophysiological events of the condition and sequences of dysfunction remain unclear. The loss of dopaminergic neurons and reduced levels of striatal dopamine are descriptions used interchangeably as underlying the motor deficits in Parkinson’s disease. However, decades of research suggest that dopamine release deficits in Parkinson’s disease do not occur only after cell death, but that there is dysfunction or dysregulation of axonal dopamine release before cell loss. Here we review the evidence for dopamine release deficits prior to neurodegeneration in Parkinson’s disease, drawn from a large and emerging range of Parkinson’s disease models, and the mechanisms by which these release deficits occur. The evidence indicates that impaired dopamine release can result from disruption to a diverse range of Parkinson’s disease-associated genetic and molecular disturbances, and can be considered as a potential pathophysiological hallmark of Parkinson’s disease.”

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”Closing remarks

Parkinson’s disease is characterized by the degeneration of the nigrostriatal pathway and loss of DANs in the SNpc, typically, amongst a constellation of dysfunctions in multiple systems. Robust evidence collected over several decades supports that DAN pathology manifests first as a dysfunction in DA axons that project to the dorsal striatum. In this review, we have summarized the DA release defects reported in models of Parkinson’s disease and the mechanisms by which they are currently known to occur. These defects frequently precede motor symptom onset and neuronal cell loss and seem to be now well established as a marker of Parkinson’s disease prior to degeneration. Much less well explored is whether in turn, synaptic dysfunction is a marker that only heralds imminent cellular demise as an innocent bystander, or whether, this deficit has a detrimental impact on cell viability that contributes to the disease process, catalysing disease progression through symptom onset or cell death. If DA synapse dysfunction is not simply reporting disease onset, but is supporting disease progression, then future strategies to restore axon function might in turn lead to neuroprotection. An improved understanding of the mechanisms underlying DA release deficits could therefore offer hope not just for improved symptom-treating therapies, but become a focus for the design of early neuroprotective therapeutics.”