Death in the substantia nigra: a motor tragedy

It is well known that the death of dopaminergic neurons of the substantia nigra pars compacta (SNc) is the pathological hallmark of Parkinson's disease (PD), the second most common and disabling condition in the expanding elderly population. Nevertheless, the intracellular cascade of events leading to dopamine cell death is still unknown and, consequently, treatment is largely symptomatic rather than preventive. Moreover, the mechanisms whereby nigral dopaminergic neurons may degenerate still remain controversial. Hitherto, several data have shown that the earlier cellular disturbances occurring in dopaminergic neurons include oxidative stress, excitotoxicity, inflammation, mitochondrial dysfunction and altered proteolysis. These alterations, rather than killing neurons, trigger subsequent death-related molecular pathways, including elements of apoptosis. In rare incidences, PD may be inherited; this evidence has opened a new and exciting area of research, attempting to shed light on the nature of the more common idiopathic PD form. In this review, the characteristics of the SNc dopaminergic neurons and their lifecycle from birth to death are reviewed. In addition, of the mechanisms by which the aforementioned alterations cause neuronal dopaminergic death, particular emphasis will be given to the role played by inflammation, and the relevance of the possible use of anti-inflammatory drugs in the treatment of PD. Finally, new evidence of a possible de novo neurogenesis in the SNc of adult animals and in PD patients will also be examined.