Parkinson disease, 10 years after its genetic revolution: multiple clues to a complex disorder.
Over the last 10 years, an unprecedented number of scientific reports have been published that relate to the pathogenesis of parkinsonism. Since the discovery in 1997 of the first heritable form of parkinsonism that could be linked to a mutation in a single gene, SNCA, many more genetic leads have followed (Parkin, DJ-1, PINK1, LRRK2, to name a few); these have provided us with many molecular clues to better explore the etiology of parkinsonism and have led to the dismantling of many previously held dogmas about Parkinson disease (PD). Epidemiologic studies have delineated an array of environmental modulators of susceptibility to parkinsonism, which can now be examined in the context of gene expression. Furthermore, in vivo imaging data and postmortem results have generated concepts that greatly expanded our appreciation for the phenotypic spectrum of parkinsonism from its presymptomatic to advanced stages. With this plethora of new information emerged the picture of a complex syndrome that raises many questions: How many forms of classic parkinsonism/Parkinson disease(s) are there? Where does the disease begin? What causes late-onset, "idiopathic" PD? What are the caveats related to genetic testing? What is the role of Lewy bodies? What will be the best disease model to accommodate the now known genetic and environmental contributors to parkinsonism? What will be the ideal markers and targets for earlier diagnosis and cause-directed therapy? In the following article we highlight some of the burning issues surrounding the understanding of classic parkinsonism, a complex puzzle of genes, environment, and an aging host.
Klein
Christine
C
Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. christine.klein@neuro.uni-leubeck.de
Schlossmacher
Michael G
MG
D000818:Animals; D004781:Environmental Exposure / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics; D005820:Genetic Testing / Q000379:methods / Q000639:trends; D006801:Humans; D009154:Mutation; D010300:Parkinson Disease / Q000209:etiology* / Q000235:genetics*