Research Highlights

Prof. dr. Arjan Kortholt

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are so far the most frequent cause of late-onset and idiopathic Parkinson’s disease and recent data suggest that, independent of mutations, increased LRKK2 kinase activity plays an essential role in the disease pathogenesis. Although, many LRRK2-specific brain-penetrant kinase inhibitors have been developed, most of them have major side effects, and none of the inhibitors cannot be used for the disease treatment yet. Therefore, targeting other domains of LRRK2 instead of the kinase domain has high potential for improved therapeutic benefits. Recently, high quality full-length LRRK2 has been purified to obtain the first structural map[1] for developing novel allosteric tools to target LRRK2 activity. In collaboration with the labs of Wim Versées (VUB, Brussels) and Johannes Gloeckner (DZNE Tübingen), a set of nanobodies have been generated that can modulate LRRK2 activity[2]. With the Kennedy lab (UGA, Athens) a set of stapled peptides have been designed that effectively disrupt LRRK2 dimerization and rescue LRRK2-mediated cell-death[3, 4]. Currently, the Kortholt lab is working together with these academic partners and companies to further develop these and other compounds that allosterically regulate LRRK2 activity, with the goal to bring them into the clinic.

[1] Guaitoli et al., 2016, Proc Natl Acad Sci U S A; 113(30):E4357-66. doi: 10.1073/pnas.1523708113.

[2] Singh et al., 2022, Proc Natl Acad Sci U S A.;119(9):e2112712119. doi: 10.1073/pnas.2112712119.

[3] Helton et al., 2021, ACS Chem Biol.;16(11):2326-2338. doi: 10.1021/acschembio.1c00487.

[4] Pathak et al., 2023, ACS Chem Neurosci.doi: 10.1021/acschemneuro.3c00259.