prof. dr. A. (Arjan) Kortholt

One of the major focuses of my lab is the biochemical and to structural characterization of G-proteins.  I am particularly interested in the structure and function of LRRK2, whose mutations are the most common genetic linkage with familial forms of Parkinson’s disease. LRRK2 belongs to the Roco family of proteins, which are characterized by the presence of a Ras-like G-domain called Roc, a dimerization domain called COR and a kinase domain. Parkinson-associated mutations have been found in the Roc, COR and kinase domains, all resulting in increased kinase activity and decreased GTPase activity. Several brain-penetrant kinase inhibitors have been identified that are selective for LRRK2. However, long-term inhibition of LRRK2 with these inhibitors causes, severe kidney and lung abnormality, similar to disrupting LRRK2 in mice. Furthermore, different PD mutations in LRRK2 probably have different defects in the activation mechanism of LRRK2 and it is unclear if all pathogenic effects are mediated via the kinase domain as a common denominator of disease. Therefore, we are focusing on alternative approaches that target other domains of LRRK2 and may have significantly improved therapeutic benefits.

My lab is also interested in the molecular basis of gradient sensing and polarity in Dictyostelium.  Towards this end, we have use a combination of genetic investigations to probe the basis of gradient amplification and biochemical interaction screens to identify novel effectors of small and heterotrimeric G-protein signaling in Dictyostelium.