Molecular Mechanisms of Parkinson Disease
Team: Aleksandar Rakovic (Group leader), Katharina Shurkewitsch (MD student), Jannik Prasuhn (MD student), Jonathan Ziegler (MD student), Christoph Mårtensson (MS student)
The main focus of the team “Molecular Mechanisms of Parkinson’s Disease” is the characterization of molecular pathways involved in the pathophysiology of Parkinson’s disease (PD) using human cellular models (human dermal fibroblasts, neuroblastoma cell lines and induced pluripotent stem cell (iPSC)-derived neurons). We investigate the interaction between the mitochondrial kinase PINK1 (PTEN-induced putative kinase 1) and the ubiquitin E3 ligase Parkin and their role in the removal of damaged mitochondria by autophagy (mitophagy). Previoiusly we discovered that PD-causing mutations in PINK1 impair recruitment of Parkin to damaged mitochondria and demonstrated the role of Parkin in the ubiquitination of outer mitochondrial membrane proteins as an initial step in mitophagy. Currently, we focus on depicting the exact role of the ubiquitin proteasome system and the lysosomal system in mitophagy.
Recently, we established a platform for genome editing using CRISPR/Cas9 system in various cellular models. For this, we are using episomal vectors for expressing both Cas9 protein and guide RNA (gRNAs) as well as in-vitro synthesized “capped” Cas9 mRNA and gRNAs for an integration-free approach.
In addition and in collaboration with Dr. Krishan Vishnolia (Institute of Integrative und Experimental Genomic (IIEG), University of Lübeck), we have generated PINK1 and Parkin knockout Zebrafish (Danio rerio) models of PD using CRISPR/Cas9 . Since 2014, we have been closely collaborating with Dr. Melissa Vos (Institute of Neurogenetics, University of Lübeck) on pink1 and parkin knockout Drosophila models.
Projects are funded by intramural grant support, the DFG, and by the Hermann and Lilly Schilling Foundation.
We collaborate with several national and international colleagues including Prof. Dimitri Krainc (Northwestern University, Feinberg School of Medicine, USA), Prof. Bart de Strooper (University of Leuven, Leuven, Belgium), the SysMed Consortium (Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg), Prof. Sonja Schrepfer (Hamburg Transplant and Stem Cell Immunobiology Laboratory, University of Hamburg, Germany).