The genetics of Early Onset ParkinsonismMaria G. Macedo


Parkinson’s disease (PD) occurs in 1-2% of people after their sixties and causes slowing of movements, tremors and stiffness, but also dementia and mood disorders. In the brain, there is a loss of cells which use Dopamine for signalling. Replacing dopamine can alleviate the motor symptoms, but is no cure.
Novel therapies require better facts on the origins of PD, and worldwide, errors in more than 18 genes were found. Our contribution started with the first scanning of 5 genes in 187 Dutch patients with familial or early onset (before 50 years). A genetic cause was present in 4% of this group.

Our search for unidentified genetic risk factors continued by detailed analysis of the chromosomes for small DNA errors, like duplications or losses. We identified 30 such DNA variants occurring more often in PD patients. Some of these regions include genes, active in cell-detoxification, signal-transmission and immune response.

The effect of an abnormal DJ-1/PARK7 gene in a cell was another important result. The mutant/abnormal protein moves inside the cell’s nucleus near the DNA and the mitochondria (the respiratory factory of the cell) whereas the normal protein is spread all over the cell. Moreover, chemical tests show how short-lived and unstable this mutant protein is.
Gene identification and functional analysis are essential for improving genetic diagnosis and genetic counseling for PD and on the road towards any future therapeutic molecule. Patients and families will need ample patience while gradually such a road becomes marked.