International scientific articles 2003

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease, with a prevalence of almost 2% in people aged 65 and over. Due to the ageing of the population in western countries, the social burden of PD will dramatically increase in the forthcoming years.

The causes of PD remain mostly unknown. The disease is usually sporadic (non-familial), or it runs in families without a clearcut mendelian pattern, implying a complex etiology (several genetic and non-genetic factors implicated). More rarely, PD is transmitted as a simple genetic trait, following the classical Mendelian laws. By analysing these rare, familial PD forms, we can identify the underlying genetic defects. These abnormal genes, in turn, point to specific molecular mechanisms, which can be implicated in the common non-hereditary forms of PD as well. Until now, two genes have been firmly implicated in PD: alpha-synuclein and parkin.

Genetically isolated populations are increasingly recognized as a powerful framework for research aimed at the identification of genetic factors underlying complex disorders. Since isolated populations originate from a limited number of founders, they are characterized by a simpler genetic make-up compared to the general population; this can greatly facilitate the identification of genes for complex diseases, such as PD.

By studying a genetically isolated population in the South West of the Netherlands, we have recently localized the genetic defect in a novel familial form of PD, named PARK7, to the short arm of chromosome 1; later we have cloned DJ-1 as the responsible gene at the PARK7 locus.

Our discovery that the DJ-1 gene is defective in PARK7 represents a new step forward to dissect the molecular mechanisms underlying PD, and ultimately to develop new strategies for therapy.

The protein encoded by the DJ-1 gene has been highly conserved in evolution, suggesting an important cellular role. The function of the DJ-1 protein is still unknown, but preliminary evidences suggest its involvement in the cell protection against oxidative stress. This is interesting because it is well known that oxidative damage occurs in the brain in classical PD forms.

Until now, the DJ-1 gene had not been implicated in brain functions or brain diseases. Our findings offer therefore a novel clue for understanding of the role of this gene and the DJ-1 protein for the normal brain. Furthermore, elucidating why defects in the DJ-1 function lead to parkinsonism will facilitate our understanding of the pathogenesis of the common forms of PD.