A global view of Parkinson's disease pathogenesis: implications for natural history and neuroprotection

Neuroprotection in PD remains the most important goal of current research. Most of presently used strategies are directed at interfering with signalling pathways involved in neuronal death. However, the influence of compensatory alterations in neurotransmitter receptors and related signalling pathways, as well as the role of aging and associated lesions, are not taken into consideration. Their progressive failure might contribute to the appearance and/or progression of the disease. Thus, early restoration of basal ganglia physiology will support the compensatory events and delay the irreversible modification of circuitry that characterizes the clinical progression of PD. Enhancing neuronal plasticity and avoiding the negative effects of aging and associated lesions might help the remaining neural circuits to compensate for lost or broken circuits and improve overall network performance and neurological function. These modulating factors represent potential targets for therapeutic intervention resulting in lasting clinical benefit for the patient. The concept of neuroprotection should be modified, shifting the focus from neurons that are lost to those that survive.