title: LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are linked to familial as well as sporadic forms of Parkinson's disease (PD), a neurodegenerative disease characterized by dysfunction and degeneration of dopaminergic and other types of neurons. The molecular and cellular mechanisms underlying LRRK2 action remain poorly defined. Here, we show that LRRK2 controls synaptic morphogenesis at the Drosophila neuromuscular junction. Loss of Drosophila LRRK2 results in synaptic overgrowth, whereas overexpression of Drosophila LRRK or human LRRK2 has opposite effects. Alteration of LRRK2 activity also affects neurotransmission. LRRK2 exerts its effects on synaptic morphology by interacting with distinct downstream effectors at the presynaptic and postsynaptic compartments. At the postsynapse, LRRK2 interacts with the previously characterized substrate 4E-BP, an inhibitor of protein synthesis. At the presynapse, LRRK2 phosphorylates and negatively regulates the microtubule (MT)-binding protein Futsch. These results implicate synaptic dysfunction caused by deregulated protein synthesis and aberrant MT dynamics in LRRK2 pathogenesis and offer a new paradigm for understanding and ultimately treating PD.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Seongsoo
authors.initials: S
authors.lastname: Lee
authors.forename: Hsin-Ping
authors.initials: HP
authors.lastname: Liu
authors.forename: Wei-Yong
authors.initials: WY
authors.lastname: Lin
authors.forename: Huifu
authors.initials: H
authors.lastname: Guo
authors.forename: Bingwei
authors.initials: B
authors.lastname: Lu
mesh_terms: D000818:Animals; D004330:Drosophila / Q000254:growth & development*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055369:Miniature Postsynaptic Potentials / Q000502:physiology*; D009024:Morphogenesis / Q000235:genetics*; D009154:Mutation; D009469:Neuromuscular Junction / Q000166:cytology / Q000502:physiology*; D010448:Peptide Initiation Factors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D013569:Synapses / Q000378:metabolism* / Q000502:physiology
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D010448:Peptide Initiation Factors; C410006:Thor protein, Drosophila; C409635:futsch protein, Drosophila; C543697:LRRK protein, Drosophila; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases