Physiology versus pathology in Parkinson's disease

Abstract

Over the last few years, human genetics has provided a series of invaluable entry points to understanding the pathogenesis of Parkinson's disease (PD). Relative to dominantly inherited forms of PD caused by mutations in the proteins α-synuclein and leucine-rich repeat kinase 2 (LRRK2), recessive forms of PD do not seem to bear as close a resemblance to the sporadic disorder. Mutations in parkin produce a distinctive, early onset clinical syndrome with slower progression than the idiopathic disorder (1). Parkin functions as an E3 ubiquitin ligase, suggesting a role in targeting to the proteasome and protein turnover. Considering this biochemical activity, it is surprising that the pathology associated with mutations in parkin shows no Lewy bodies or obvious protein deposits. Indeed, ubiquitination by parkin may control other cellular processes such as endocytosis (2). Nonetheless, mutations in parkin do result in the loss of midbrain dopamine neurons. Mutations in the protein DJ-1 implicated in the response to oxidative stress also produce recessive parkinsonism (3, 4), but there is very little if any pathology available. Although the condition responds to dopamine replacement therapy, we do not know whether it actually involves a loss of dopamine neurons. Similarly, mutations in the PTEN-induced putative kinase 1 (PINK1), the subject of the paper by Kitada et al. in a recent issue of PNAS (5), cause a form of recessive parkinsonism (6), but its pathological basis also remains to be characterized. Nonetheless, a significant number of patients with later-onset parkinsonism that strongly resembles idiopathic PD have heterozygous, or occasionally homozygous, mutations in parkin, DJ-1, and PINK1 (7), supporting their relationship to the sporadic disorder.