Update on the pathogenesis of Parkinson's disease

Parkinson's disease is a primarily sporadic occurring neurodegenerative disorder of advanced age. However, in the last few years several genes have been identified that lead to a hereditary parkinsonian disorder with autosomal dominant or autosomal recessive inheritance. This includes autosomal dominant mutations in the alpha-synuclein, ubiquitin-C-terminal hydrolase-L1 (UCH-L1) and the leucine-rich repeat kinase (LRRK)2 genes and autosomal recessively inherited mutations in Parkin, PINK1, DJ-1 and the ATP13A2 genes. By taking the biochemical function of these genes and mutations into account, three underlying pathogenetic pathways can be identified: (i) altered protein quality control, (ii) oxidative stress and mitochondrial dysfunction, and (iii) disturbed kinase activity. It remains an open question whether alterations of these pathways lead to different entities of Parkinson's disease or whether they finally converge at a point that is the common pathogenetic denominator of Parkinson's disease. Finally cell death is executed by excitotoxicity, apoptosis and autophagy and appears to be facilitated by neuroinflammatory processes.