Molecular Biology of Retinal Degenerations
Functional Genomics - learning from protein complexes analysis of the Parkinson's Disease Protein LRRK2
Mutations in the Leucine-rich Repeat Kinase 2 gene (LRRK2) are the single most common cause for inherited Parkinson's Disease (PD). LRRK2 is large protein consisting of several domains with different functions. Beside enzymatically active domains, able to modify other proteins, it contains others allowing protein-protein interactions. Therefore the project aims at understanding how LRRK2 interacts with other proteins in the cell, how these interactions differ between normal and mutated versions of the gene, and how these differences impact the development and progression of PD.
For this purpose, LRRK2-associated protein complexes are systematically isolated from cell culture and tissues by affinity-based purification methods and subsequently analyzed by high end mass spectrometry. To represent the endogenous situation as closely as possible, in collaboration with the group of Thomas Gasser (Hertie Institute for Clinical Brain Research, Tübingen) patient-derived induced human pluripotent stem cells (hiPSC) differentiated into neurons are used. This model allows to study LRRK2 within the context of an individual patient-derived protein repertoire. Following the idea of "guilt-by-association" the identified LRRK2 interacting proteins will be assigned to cellular functions by bioinformatic meta-analysis. By deciphering LRRK2 protein interaction networks we aim at getting better mechanistic insights into its function on a molecular level. The rationale behind this approach is to use these protein interaction networks to identify LRRK2-depentent cellular pathways and to understand how they are affected in Parkinson's Disease. The successful identification of cellular pathways which are affected by LRRK2 mutations could finally be used to consider rational therapeutic strategies for the treatment of LRRK2-associated PD.