Life on the Edge: Determinants of Selective Neuronal Vulnerability in Parkinson’s Disease

Abstract

One of the defining features of Parkinson’s disease (PD) is its sparsely distributed pathology. This chapter explores the hypothesis that this selective vulnerability can be traced back to an unusual neuronal phenotype. This phenotype is best exemplified by dopaminergic neurons in the substantia nigra pars compacta (SNc), whose loss is responsible for the cardinal motor symptoms of PD. These neurons have extraordinarily long and branched axons, sustained autonomous spiking, and elevated levels of cytosolic Ca²⁺, in addition to a chemically reactive neurotransmitter. This combination of features leads to sustained elevations in mitochondrial oxidative stress, possibly as a consequence of the reliance on feed-forward control of mitochondrial metabolism, and to increased susceptibility to alpha-synuclein (aSYN) aggregation. These derivative features could increase the impact of aging, genetic mutations, and environmental toxins linked to increased risk of PD, providing a unifying theory of PD pathogenesis. Although most of these traits are not amenable to therapeutic manipulation, Ca²⁺ loading is indeed, because it stems from opening of Cav1 (L-type) Ca²⁺ channels – channels that are antagonized by dihydropyridine drugs long used for the treatment of hypertension. Epidemiological studies have revealed that the use of dihydropyridines is associated with a reduced risk of developing PD. As a consequence, a large phase III clinical trial is underway in North America to determine if one of the dihydropyridines (isradipine) can slow PD progression.