Chemical Genetic Targeting of the LRRK2 GTPase Domain
Genetic variants throughout the multi-domain protein leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal dominant Parkinson's disease, and the most prevalent Parkinson's-associated LRRK2 variants enhance kinase activity. Hence, the kinase domain has been extensively targeted for therapeutic development. However, clinical progression of LRRK2 kinase inhibitors has been…
The human protein LRRK2 possesses a Roc-COR GTPase domain along with a kinase domain, with the GTPase domain playing a role in intramolecular regulation of kinase output. Researchers explored the possibility of targeting the Roc-COR GTPase domain as an alternative method to reduce LRRK2 kinase activity. By employing a chemical genetic technique, they discovered that sensitizing LRRK2 to existing GTPase inhibitors could decrease LRRK2-mediated phosphorylation of Rab10 in cells, although it did not completely inhibit the activity.
This preliminary research establishes a foundation for future endeavors aimed at developing pharmacological inhibitors targeting the LRRK2 GTPase, offering a novel approach for therapies addressing Parkinson's disease driven by LRRK2.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
