Molecular pathogenesis

Idiopathic Parkinson's disease (IPD) is the second most common neurodegenerative disorder after Alzheimer's disease and affects approximately 1% of the people 55 years of age. IDP is characterized by the following cardinal symptoms:

• Akinetic rigidity
• Tremor
• Reduced startle reflexes

The symptoms arise from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) in the midbrain, causing a dopamine shortage in the striatum. Other dopaminergic, noradrenergic and serotonergic systems are also effected, but not in this extend. Another neuropathological hallmark, seen in the affected regions in most patients, is the presence of Lewy bodies, intracellular ubiquinated protein aggregates. The ethiology of IPD still remains unclear, however, environmental factors, mitochondrial defects and genetic factors either alone or together, have been implicated in the disease.

The role of genetic factors in typical PD has been discussed for a long time, however, nowadays it is widely accepted that approx. 20% of PD cases have a positive family history. Based on large families where PD has a mendelian inheritance, 16 gene loci (PARK 1-16) have been mapped and 6 of these genes have a causal role in the pathogenesis of the disease.  The proteins encoded by these genes play a role in the ubiquitin dependent protein degradation and/or in intracytoplasmic protein aggregation (alpha-synuclein, Parkin, UCH-L1). Therefore, a dysfunction of the ubiquitin proteasome system might play a role in the pathogenesis of PD.

The functional characterization of mutations in pathogenic genes in autosomal recessive inherited PD (Parkin, PINK1, DJ-1), shows, in addition to the involvement of the ubiquitin dependent protein degradation, an impairment in the mitochondrial homeostasis as a possible cause for the degeneration of dopaminergic neurons.  Functional investigations of PINK1 (PARK6) have shown mitochondrial dysfunction when mutant PINK1 is present, which leads to more sensitivity towards cellular stress. This is also the case for DJ-1 (PARK7), where in vitro studies have implicated a role in maintaining the mitochondrial function and the involvement of DJ-1 in the oxidative stress response of cells. Finally, our results, investigating mutations in Omi/HtrA2 (PARK13), further support the role of mitochondrial dysfunctions in the pathogenesis of PD.