Parkinson Disease

Parkinson´s disease (PD) represents the most common neurodegenerative movement disorder. The disease is characterized by a non-motor phase characterized by olfactory deficits, sleep disturbances, obstipation and psychiatric symptoms. This phase can last for decades before the major motor symptoms occur. The latter diagnosis is only taking place when already more than 60% of dopaminergic neurons are lost. Thus research into the non-motor phase (prodromal) is urgently needed to improve diagnosis and/or slow down or prevent the progression of the disease. Indeed, despite being able to attenuate symptoms of PD for some time there is no definitive cure. The aetiology is known to be multifactorial including influence of genetics, environment (i.e. stress) and age.

In order to increase our understanding of the molecular mechanisms underlying the aetiology and progression of the disease the PD team generates genetic mouse models carrying deletions or mutations in the genes known to be associated with PD. In collaboration with the EUCOMM team we have by now generated knock-outs, conditional mutants and mice expressing pathogenic mutations of 18 PD associated genes. Presently, we are focusing our efforts on the analysis of LRRK2, PINK1, and DJ-1 models. In collaboration with the neurobehavior team we comprehensively analyze these models in respect to behavior and morphology. All models analyzed so far exhibit gene specific symptoms of the prodromal phase of the disease, thus are ideal models to study early pathological molecular changes. These studies are supported by cellular and molecular characterization of PD-patient specific induced pluripotent stem cells (iPSCs). In both model systems we focus on aberrant mitochondrial function (e.g. bioenergetics, mitochondrial trafficking), changes in metabolism and microglia function.

In addition we study the function of developmental genes in adulthood. These investigations are driven by recent findings that genes involved in the generation of dopaminergic neurons - such as Engrailed or components of the Wnt-pathway - exhibit neuroprotective functions in adulthood. Furthermore, we also work towards novel cell replacement strategies, such as the direct conversion of astrocytes into dopaminergic neurons.

With the newly acquired knowledge of the molecular and systemic phenotypes of preclinical models of PD we contribute to the development and discovery of new and better diagnosis and therapies for this still incurable disease.

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