Abstract
Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene are linked to autosomal dominant Parkinson's disease (PD), and genetic variations at the LRRK2 locus are associated with an increased risk for sporadic PD. This gene encodes a kinase that is physiologically multiphosphorylated, including clusters of both heterologous phosphorylation and autophosphorylation sites. Several pieces of evidence indicate that LRRK2's phosphorylation is important for its pathological and physiological functioning. These include a reduced LRRK2 heterologous phosphorylation in PD brains or after pharmacological inhibition of LRRK2 kinase activity as well as the appearance of subcellular LRRK2 accumulations when this protein is dephosphorylated at heterologous phosphosites. Nevertheless, the regulatory mechanisms governing LRRK2 phosphorylation levels and the cellular consequences of changes in LRRK2 phosphorylation remain incompletely understood. In this review, we present current knowledge on LRRK2 phosphorylation, LRRK2 phosphoregulation, and how LRRK2 phosphorylation changes affect cellular processes that may ultimately be linked to PD mechanisms.
Highlights
Parkinson’s disease (PD) is the most common motor neurodegenerative disease, and the gene encoding the protein Leucine Rich Repeat Kinase 2 (LRRK2) is considered one of the most important genetic risk factors for PD (Nalls et al, 2019)
2010; LRRK2 G2019S assayed for Webber et al, 2011; Sheng autophosphorylation followed by et al, 2012; Law et al, 2014) analysis by LC-MS/MS
This study reports that LRRK2 interacts with all three subunits of phosphatase 2A (PP2A) and that this is mediated by the ROC domain in cultured cells
Summary
Parkinson’s disease (PD) is the most common motor neurodegenerative disease, and the gene encoding the protein Leucine Rich Repeat Kinase 2 (LRRK2) is considered one of the most important genetic risk factors for PD (Nalls et al, 2019). LRRK2 encodes a 286-kDa multi-domain protein of 2527 amino acids harboring two enzymatic activities, a kinase domain “KIN” and a GTPase domain named a Ras Of Complex proteins “ROC” (Figure 1). These two domains are connected via a C-terminal of ROC “COR” domain. Most LRRK2 PD mutations are located in the catalytic core of the protein: in the ROC domain (N1437H, R1441C/G/H/S), in the COR domain (Y1699C), and in the kinase domain (G2019S, I2020T) (Funayama et al, 2005; Healy et al, 2008; Aasly et al, 2010; Mata et al, 2016; Nucifora et al, 2016). LRRK2 exists as a phosphorylated protein in mammalian cells under basal conditions as observed after metabolic labeling of LRRK2-expressing cells with radioactive phosphate or by TABLE 1 | Reported LRRK2 phosphorylation sites
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
