PROGRESSIVE GENETICALLY CONTROLLED DOPAMINERGIC NEURONS APOPTOSIS IN SUBSTANTIA NIGRA: RELEVANCE FOR PARKINSON DISEASE?

Parkinson's disease (PD) is caused by degeneration of the dopaminergic neurons of the substantia nigra (SNc). Patients with PD have sensory abnormalities that often precede the onset of locomotor deficits. The early appearance of sensory deficits questions about the link between pain symptoms and SNc degeneration. Unfortunately, early PD symptoms are difficult to study in humans asymptomatic for motor deficits. Therefore, there is a need to develop a pre-clinical model adapted to the study of PD-related pain symptoms at the onset of degeneration. In PD, SNc dopaminergic neurons degenerate primarily through apoptosis following an increase in Caspase-3 activity. Therefore, temporally and locally manipulating Caspase-3 activity in SNc neurons would offer an avenue to study the progressive consequences of dopaminergic neuron apoptosis. The first observations in animals reveals that strong induction of taCasp3 leads to SNc degeneration, causes locomotor deficit, and induces mechanical sensory hypersensitivity. Next, the effects of a progressive ablation lead to a sequential appearance of somatosensory deficits, including tactile allodynia, largely before the onset of motor symptoms. Pharmacological treatments shows that the use of a brain penetrant T-type calcium channel inhibitor is able to acutely reverse the tactile hypersensitivity in this model.
Potentially, this preclinical approach may offer a better way to recapitulate the course of clinical sensory and motor signs of PD and notably better asses the underlying pain pathophysiological mechanisms and potential new pharmacological treatments efficient for the distinct symptoms of PD.