Parkinson’s Desease

Parkinson’s disease is the most common degenerative disorder after Alzheimer’s disease. Its prevalence is estimated to be about 1% of the population older than 60 years. Its clinical cardinal features are bradykinesia, tremor, and rigidity. The pathological hallmark is the occurrence of Lewy bodies in the mesencephalon. Although originally considered to be sporadic, several families with autosomal-dominant or autosomal recessive inheritance as well as several genes causing Parkinson’s disease have been identified. These gene identifications have fueled the research and our knowledge on the molecular pathogenesis of Parkinson’s disease. The results have put Parkinson’s disease in line with other neurodegenerative disorders in which protein aggregates are a common hallmark of the disease.
Laboratory work concentrates on the formation, relevance and function of protein aggregates and the question of whether protein aggregates themselves are toxic or protective, on the role of oxidative stress and electrophysiological changes in Parkinson’s disease models.

Protein Aggregates

Lewy bodies are cytoplasmic inclusions of fibrillary protein aggregates, consisting of alpha-synuclein and other proteins. They are characteristically found in the brains of patients with Parkinson’s disease (PD) but also in a number of other conditions termed synucleinopathies (Dementia with Lewy bodies, Pure autonomic Failure, Multi System Atrophy). Protein aggregation can result from an increased tendency of misfolded protein to aggregate or from an impairment of protein degradation by the ubiquitin proteasome system. Mutations in the alpha-synuclein gene that increase its tendency to misfold and aggregate, and also mutations in genes involved in proteasomal protein degradation have been found to be responsible for inherited forms of PD. This suggests that protein aggregation may play an important role in the pathogenesis of PD in general. It remains unclear, however, whether full-blown Lewy bodies or oligomere precursors termed protofibrils are responsible for neurotoxicity.

We are currently using the MPTP model and genetically modified mice expressing mutant human A30P-alpha-synuclein, the latter which causes autosomal dominant PD in humans. By expressing proteins favouring or inhibiting protein aggregation through viral gene transfer, we are investigating the selective vulnerability of certain cell types and that the connections between oxidative stress and protein aggregation, and between protein aggregation and neurotoxicity. At the same time we are exploring pharmacological and genetic strategies for neuroprotective therapy.

Oxidative Stress

Members of the laboratory played an instrumental role in identifying oxidative stress, especially nitric oxide derived from nNOS or iNOS, as an important mediator of cellular dysfunction and cell death in Parkinson’s disease and other models of neurodegenerative disorders.

Electrophysiology

Pathopysiology of basal ganglia output:

Traditionally, the motor symptoms of Parkinson’s disease (PD) have been explained by dopamine depletion in the striatum. Dopamine is not only released in the striatum, however, but also in other nuclei of the basal ganglia. We study the controversial mechanism of dopamine release in the substantia nigra pars reticulata (SNr) and its effect on the spatial distribution of activity in this basal ganglia output nucleus. Our aim is to elucidate the role of the local synaptic connectivity for the pathogenesis of PD and to explore new symptomatic and neuroprotective strategies for the therapy of PD.

Methods we employ in this research include: electrophysiology, pharmacology, viral gene transfer, cell and molecular biology in brain slices and animal models of Parkinson’s disease.