Regulation of LRRK2 by Phosphatases

LRRK2 is a highly phosphorylated protein, and evidence of a physiological role for LRRK2 phosphorylation has accumulated in recent years for cellular phosphosites, many of which are found in the ANK-LRR interdomain region, i.e., the S910/S935/S955/S973 sites as well as recently for autophosphorylation sites, at least one of which has been confirmed in cells, S1292. LRRK2 phosphorylation is modulated in several disease or potential therapy relevant conditions such as in disease mutant variants of LRRK2 or following LRRK2 kinase inhibitor treatment. This chapter will focus on the regulation of LRRK2 phosphorylation and more specifically the role of phosphatases in LRRK2 dephosphorylation. This will include reviewing the conditions in which LRRK2 is found to be dephosphorylated, the molecular partners and phosphatases involved in regulating LRRK2 phosphorylation, as well as discussing how LRRK2 phosphatases may be therapeutic targets or biomarkers in their own right.