title: The synaptic function of LRRK2.
abstract: Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most frequent genetic lesions so far found in familial as well as sporadic forms of PD (Parkinson's disease), a neurodegenerative disease characterized by the dysfunction and degeneration of dopaminergic and other neuronal types. The molecular and cellular mechanisms underlying LRRK2 action remain poorly defined. Synaptic dysfunction has been increasingly recognized as an early event in the pathogenesis of major neurological disorders. Using Drosophila as a model system, we have shown that LRRK2 controls synaptic morphogenesis. Loss of dLRRK (Drosophila LRRK2) results in synaptic overgrowth at the Drosophila neuromuscular junction synapse, whereas overexpression of wild-type dLRRK, hLRRK2 (human LRRK2) or the pathogenic hLRRK2-G2019S mutant has the opposite effect. Alteration of LRRK2 activity also affects synaptic transmission in a complex manner. LRRK2 exerts its effects on synaptic morphology by interacting with distinct downstream effectors at the pre- and post-synaptic compartments. At the postsynapse, LRRK2 functionally interacts with 4E-BP (eukaryotic initiation factor 4E-binding protein) and the microRNA machinery, both of which negatively regulate protein synthesis. At the presynapse, LRRK2 phosphorylates and negatively regulates the microtubule-binding protein Futsch and functionally interacts with the mitochondrial transport machinery. These results implicate compartment-specific synaptic dysfunction caused by altered protein synthesis, cytoskeletal dynamics and mitochondrial transport in LRRK2 pathogenesis and offer a new paradigm for understanding and ultimately treating LRRK2-related PD.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, R270 Edwards Building, Stanford, CA 94305, U.S.A.
authors.forename: Seongsoo
authors.initials: S
authors.lastname: Lee
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Imai
authors.forename: Stephan
authors.initials: S
authors.lastname: Gehrke
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.forename: Bingwei
authors.initials: B
authors.lastname: Lu
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C543697:LRRK protein, Drosophila; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases