title: Leucine-rich repeat kinase 2 (LRRK2) cellular biology: a review of recent advances in identifying physiological substrates and cellular functions.
abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common forms of inheritable Parkinson's disease and likely play a role in sporadic disease as well. LRRK2 is a large multidomain protein containing two key groups, a Ras-like GTP binding domain and a serine, threonine kinase domain. Mutations in the LRRK2 gene that associate with Parkinson's disease reside primarily within the two functional domains of the protein, suggesting that LRRK2 function is critical to the pathogenesis of the disease. The most common LRRK2 mutation increases kinase activity, making LRRK2 kinase inhibition an attractive target for small molecule drug development. However, the physiological function of LRRK2 kinase as well as its endogenous protein substrates remains poorly understood and has hindered drug development efforts. Recent advances in LRRK2 biology have revealed several potential cellular roles, interacting proteins, and putative physiological substrates. Together, a picture emerges of a complex multifunctional protein that exists in multiple cellular compartments. Through unclear mechanisms, LRRK2 kinase regulates cytoskeleton architecture through control of protein translation, phosphorylation of cytoskeletal proteins, and response to cellular stressors. This article will briefly cover some interesting recent studies in LRRK2 cellular biology and highlight emerging cellular models of LRRK2 kinase function.
authors.affiliation: Department of Neurosymptomatic Disorders, Department of Chemistry, Modeling, and Informatics, Merck Research Laboratories, Merck & Co, West Point, PA 19486, USA. robert_drolet@merck.com
authors.forename: Robert E
authors.initials: RE
authors.lastname: Drolet
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Kern
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D014176:Protein Biosynthesis / Q000235:genetics; D046188:Protein Modification, Translational / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D013379:Substrate Specificity / Q000235:genetics / Q000502:physiology
chemical_list: D003598:Cytoskeletal Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases