Biosketch

Prof. dr. Arjan Kortholt

Arjan Kortholt studied Chemistry and received his PhD degree from the University of Groningen in 2009. During his PhD, he studied the molecular mechanisms of eukaryotic cell movement and the role of small G-proteins in the navigation in gradients of diffusive molecules. In 2007, he started working on the biochemical and structural characterization of small G-proteins in the laboratory of Prof. Wittinghofer (MPI Dortmund). In 2009, he received a Research Fellowship of the Alexander von Humboldt Foundation and since 2010 he has been appointed as associate professor at GBB, University of Groningen. A major topic in the Kortholt lab in the recent years has been therapeutic targeting of LRRK2-mediated Parkinson’s Disease (PD). He has used a combination of biochemistry and structural characterization to optimize LRRK2 inhibitor binding. These projects have been executed in close collaboration with industry (Merck; GlaxoSmithKline). He has in addition to human LRRK2, successfully used related Roco proteins from other organism to understand the complex structure and regulatory mechanism of LRRK2. Recently, high quality full-length LRRK2 has been purified and with an integrative structural biology Arjan’s team was able to obtain the first structural map of full-length LRRK2. This work contributed to the identification of LRRK2 activity modulating nanobodiess and stapled peptides, on which also a joined patent has been approved. In addition, he investigates the molecular basis of gradient sensing and polarity in the model organism Dictyostelium and human neutrophils. Towards this end, he has used a combination of genetics, microscopy and biochemical interaction screens to identify key regulators of chemotaxis.

Three top publications 2017-2022

1. Singh RK, Soliman A, ………, Herberg FW, Kortholt A*, Gloeckner CJ* & Versées W* (2022). Nanobodies as allosteric modulators of Parkinson's disease-associated LRRK2. Proceedings of the National Academy of Science USA 119(9): e2112712119; DOI: https://doi.org/10.1073/pnas.2112712119

In this study we have generated and characterized a set of LRRK2 specific Nanobodies that are important tools to study the function of LRRK2 and lead compounds for PD therapeutics

2. Helton LG, Soliman A, …….., Rideout H, Kortholt A* & Kennedy EJ* (2021). Allosteric inhibition of Parkinson's-linked LRRK2 by constrained peptides. ACS Chemical Biology 16(11): 2326-2338; DOI: https://doi.org/10.1021/acschembio.1c00487

In this study we have designed and synthesized together with the Kennedy lab (University of Georgia, USA) cell permeable stapled peptides that target LRRK2 dimerization and downregulate LRRK2 kinase activity.

3. Deyaert E, Wauters L, …….., Efremov R, Kortholt A* & Versées W* (2017) A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover. Nature Communications 8(1): 1008; DOI: https://doi.org/10.1038/s41467-017-01103-4

This study provides insights into the conformational cycle of Roco proteins and suggests a link between oligomerization and disease-associated mutations in LRRK2.