Chemical genetic approach identifies microtubule affinity-regulating kinase 1 as a leucine-rich repeat kinase 2 substrate

Mutations in leucine-rich repeat kinase2 ( LRRK2) are the most common cause of autosomal-dominant forms of Parkinson’s disease. LRRK2is a modular, multidomain protein containing 2 enzymatic domains, including a kinasedomain, as well as several protein-protein interaction domains, pointing to a role in cellular signaling. Although enormous efforts have been made, the exact pathophysiologic mechanisms of LRRK2are still not completely known. In this study, we used a chemical geneticsapproach to identify LRRK2substrates from mouse brain. This approach allows the identification of substrates of 1 particular kinasein a complex cellular environment. Several of the identified peptides are involved in the regulation of microtubule (MT) dynamics, including microtubule-associating protein(MAP)/microtubule affinity-regulating kinase1 (MARK1). MARK1 is a serine/threonine kinaseknown to phosphorylate MT-binding proteins such as Tau, MAP2, and MAP4 at KXGS motifs leading to MT destabilization. In vitro kinasea...