CHAPTER 4 - What causes the death of dopaminergic neurons in Parkinson’s disease?

The factors governing neuronal loss in Parkinson’s disease (PD) are the subject of continuing speculation and experimental study. In recent years, factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease aetiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This chapter focuses on recent studies showing that the neurons at greatest risk in PD – substantia nigra pars compacta (SNc) dopamine (DA) neurons – have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of SNc DA neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cell-specific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease. Pan-cellular risk factors in Parkinson’s disease non-neuronal cell types. The four best-documented pan-cellular factors are age, genetic mutations, Studies over the past decade have made great proenvironmental toxins and inflammation. gress in identifying factors that increase disease The strongest risk factor in Parkinson’s disease risk. The vast majority of these are pan-cellular (PD) is age (Calne and Langston, 1983; de Lau factors; that is, factors that in principle have and Breteler, 2006). Disease incidence rises expoa broad, negative impact on neuronal and nentially above the age of 65. Because improve­ ments in health care are increasing life expectancy, the number of PD patients is expected Corresponding author. to grow dramatically in the coming years, reaching Tel.: 312-503-4904; Fax: 312-503-5101; E-mail: [email protected] over 2 million in the United States by 2030 DOI: 10.1016/S0079-6123(10)83004-3 59