Parkinson's disease: Exit toxins, enter genetics

Abstract

Parkinson's disease was long considered a non-hereditary disorder. Despite extensive research trying to find environmental risk factors for the disease, genetic variants now stand out as the major causative factor. Since a number of genes have been implicated in the pathogenesis it seems likely that several molecular pathways and downstream effectors can affect the trophic support and/or the survival of dopamine neurons, subsequently leading to Parkinson's disease. The present review describes how toxin-based animal models have been valuable tools in trying to find the underlying mechanisms of disease, and how identification of disease-linked genes in humans has led to the development of new transgenic rodent models. The review also describes the current status of the most common genetic susceptibility factors for Parkinson's disease identified up to today.

Fig. 1

mRNA expression patterns in the rat brain (at the level of striatum, substantia nigra/hippocampus and cerebellum) of the PARK genes α-synuclein/SNCA (PARK1), Parkin/PRKN (PARK2), Uch-L1 (PARK5), Pink1 (PARK6), Dj-1 (PARK7), Lrrk2 (PARK8) and Atp13a2 (PARK9) revealed by in situ hybridization and radioactively labeled oligo probes. All PARK genes presented in the figure have been implicated in the pathogenesis of Parkinson’s disease. Despite being involved in a common disease, they show variable levels and patterns of expression. Uch-L1 for instance is expressed by all neurons, α-synuclein/SNCA show high expression in substantia nigra, striatum and cortical areas whereas Lrrk2 shows particularly high expression in striatum, the target area of dopamine neurons. Interestingly none of the candidate genes shows a restricted expression in the dopamine system only.