Parkinson’s Disease: An Overview of Pathogenesis

Abstract

Parkinson’s disease (PD) is clinically, pathologically, and etiologically diverse and complex combinations of genetic susceptibility and environmental risk factors like age, gender, estrogen status, race/ethnicity, exposure to pesticides, and head trauma play roles in the pathogenesis. Genetic research has identified eleven PARK loci in familial cases and genotyping technology has allowed genome-wide approaches in large populations of patients with sporadic PD. Neuropathologic studies have defined and characterized more than 30 proteins with the core filament of α-synuclein in the Lewy body inclusions of idiopathic PD. Analysis of Lewy body pathology has outlined progressive disease stages in which the intracellular deposition of α-synuclein affects medullary sites before more rostral brain regions and the late stages of involvement of cortical association neurons. In PD, there is evidence of protein misfolding, aggregation, and abnormal neuronal apoptosis. Toxin-based and recent gene mutation-based animal models of PD in mammals, flies, fish, and worms have reproduced the progressive motor and non-motor deficits observed in PD patients and shown dopamine dysfunction and delayed loss of dopaminergic neurons in the substantia nigra. Oxidative stress plays a key role in the pathogenesis of PD and the demonstration of nitrated protein within Lewy bodies and neurites provides evidence of oxidative damage in the pathogenesis of PD. Reduction in the mitochondrial enzyme complex I in PD renders neurons vulnerable to unstable oxygen free radicals and causes alpha-synuclein to aggregate into fibrils and lead to dopaminergic neuronal loss. The DJ-1 gene has antioxidant function in the cellular response to oxidative stimuli and DJ-1 is oxidatively damaged in the brains of PD patients. The occurrence of a parkinsonian syndrome in families with mutations in the DJ-1 gene also supports a role for oxidative stress in the pathogenesis of PD. Therapeutic approaches that could prevent or limit oxidative reactions in PD represent a viable strategy for the development of newer antiparkinsonian drugs.