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lecture: Cell Death in Parkinson’s Disease.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of melanized, dopaminergic neurons of the substantia nigra pars compacta (SNc) projecting to the corpus striatum. Impaired dopaminergic neurotransmission along the nigrostriatal pathway translates - through articulate changes in the functional organization of the basal ganglia circuit - into profound impairment in the capacity of executing voluntary movements.

Although four decades have passed since the nigrostriatal deficit of dopamine was identified as the main neurochemical alteration responsible for PD, a primum movens for the degenerative process affecting the SNc has not yet been identified. In fact, due to the multi-factorial nature of the disease, the process leading to nigral cell death is likely to originate from the reciprocal interactions of a restricted number of favoring conditions. These would include mitochondrial defects (impaired activity of complex I, in particular), enhanced formation of reactive oxygen species leading to oxidative damage, and aberrant protein aggregation. This latter may be linked to the reduced efficiency of a mechanism specifically devoted to the intracellular degradation of altered proteins, such as the ubiquitin-proteasome pathway. The combined actions of these phenomena may disrupt the physiological dynamics of apoptosis (programmed cell death) within the SNc, thus triggering the degenerative process. The role of apoptosis in PD pathogenesis is also supported by the observation that the toxins most frequently used to replicate parkinsonian features in animal models, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine, cause nigral degeneration by triggering the apoptotic cascade. These observations have prompted extensive research for the identification of neuroprotective drugs that may counteract the phenomenon or for a better characterization of the anti-apoptotic effects of existing compounds; attempts have also been made, with positive results, to identify signs of enhanced susceptibility to apoptosis outside the central nervous system, for example in peripheral blood cells of PD patients, in a continuous search for new biomarkers of the disease.

Once the lesion in the SNc is established, the dopaminergic denervation of the striatum gives rise to a cascade of functional changes in the basal ganglia circuitry, ultimately leading to a pathological overactivity of the subthalamic nucleus (STN), the only excitatory (glutamatergic) area of the circuit. Subthalamic overactivity underlies the expression of PD motor symptoms, but may also sustain the degenerative process, through an increased excitatory drive to surviving SNc neurons. This may represent an additional pathogenic mechanism, where the primary lesion of the SNc and following subtalamic overactivity become involved in a self-maintaining vicious circle, resulting in further nigral damage. Indeed, a reduction in STN overactivity has repeatedly proven able to counteract the nigrostriatal degeneration, in animal models of PD.

The clarification of the neuroanatomical, cellular and molecular aspects of the cell death process in PD is, therefore, a fundamental task for the researchers of the field, in that it represents a pre-requisite for the identification of innovative therapeutic strategies and, potentially, of new diagnostic approaches.