title: LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction.
abstract: Parkinson's disease gene leucine-rich repeat kinase 2 (LRRK2) has been implicated in a number of processes including the regulation of mitochondrial function, autophagy and endocytic dynamics; nevertheless, we know little about its potential role in the regulation of synaptic plasticity. Here we demonstrate that postsynaptic knockdown of the fly homologue of LRRK2 thwarts retrograde, homeostatic synaptic compensation at the larval neuromuscular junction. Conversely, postsynaptic overexpression of either the fly or human LRRK2 transgene induces a retrograde enhancement of presynaptic neurotransmitter release by increasing the size of the release ready pool of vesicles. We show that LRRK2 promotes cap-dependent translation and identify Furin 1 as its translational target, which is required for the synaptic function of LRRK2. As the regulation of synaptic homeostasis plays a fundamental role in ensuring normal and stable synaptic function, our findings suggest that aberrant function of LRRK2 may lead to destabilization of neural circuits.
authors.affiliation: Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.
authors.forename: Jay
authors.initials: J
authors.lastname: Penney
authors.affiliation: Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.|Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, California 94945, USA.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Tsurudome
authors.affiliation: Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.|Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, California 94945, USA.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Liao
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, California 94945, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Kauwe
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, California 94945, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Gray
authors.affiliation: Department of Biochemistry, Goodman Cancer Research Centre, McGill University, McGill University, 1160 Pine Avenue West, Room 614, Montreal, Quebec, Canada H3A 1A3.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yanagiya
authors.affiliation: Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.
authors.forename: Mario
authors.initials: M
authors.lastname: R Calderon
authors.affiliation: Department of Biochemistry, Goodman Cancer Research Centre, McGill University, McGill University, 1160 Pine Avenue West, Room 614, Montreal, Quebec, Canada H3A 1A3.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.affiliation: Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.|Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, California 94945, USA.
authors.forename: A Pejmun
authors.initials: AP
authors.lastname: Haghighi
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D045683:Furin / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007814:Larva / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D014176:Protein Biosynthesis; D012315:RNA Caps / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases
chemical_list: D029721:Drosophila Proteins; D045683:Furin; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D050505:Mutant Proteins; D018377:Neurotransmitter Agents; D012315:RNA Caps; C495280:LRRK2 protein, human; C543697:LRRK protein, Drosophila; D017346:Protein Serine-Threonine Kinases