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LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis

(2012) NEURON. 75(6). p.1008-1021
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Abstract
LRRK2 is a kinase mutated in Parkinson's disease, but how the protein affects synaptic function remains enigmatic. We identified LRRK2 as a critical regulator of EndophilinA. Using genetic and biochemical studies involving Lrrk loss-of-function mutants and Parkinson-related LRRK2(G2019S) gain-of-kinase function, we show that LRRK2 affects synaptic endocytosis by phosphorylating EndoA at S75, a residue in the BAR domain. We show that LRRK2-mediated EndoA phosphorylation has profound effects on EndoA-dependent membrane tubulation and membrane association in vitro and in vivo and on synaptic vesicle endocytosis at Drosophila neuromuscular junctions in vivo. Our work uncovers a regulatory mechanism that indicates that reduced LRRK2 kinase activity facilitates EndoA membrane association, while increased kinase activity inhibits membrane association. Consequently, both too much and too little LRRK2-dependent EndoA phosphorylation impedes synaptic endocytosis, and we propose a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses.
Keywords
BAR DOMAIN, PARKINSONS-DISEASE, VESICLE ENDOCYTOSIS, MEMBRANE CURVATURE, SNARE-PROTEINS, ENDOPHILIN-A, MUTATIONS, FUSION, DEGENERATION, DROSOPHILA NEUROMUSCULAR-JUNCTION

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MLA
Matta, Samer, Kristof Van Kolen, Raquel da Cunha, et al. “LRRK2 Controls an EndoA Phosphorylation Cycle in Synaptic Endocytosis.” NEURON 75.6 (2012): 1008–1021. Print.
APA
Matta, S., Van Kolen, K., da Cunha, R., van den Bogaart, G., Mandemakers, W., Miskiewicz, K., De Bock, P.-J., et al. (2012). LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. NEURON, 75(6), 1008–1021.
Chicago author-date
Matta, Samer, Kristof Van Kolen, Raquel da Cunha, Geert van den Bogaart, Wim Mandemakers, Katarzyna Miskiewicz, Pieter-Jan De Bock, et al. 2012. “LRRK2 Controls an EndoA Phosphorylation Cycle in Synaptic Endocytosis.” Neuron 75 (6): 1008–1021.
Chicago author-date (all authors)
Matta, Samer, Kristof Van Kolen, Raquel da Cunha, Geert van den Bogaart, Wim Mandemakers, Katarzyna Miskiewicz, Pieter-Jan De Bock, Vanessa A Morais, Sven Vilain, Dominik Haddad, Lore Delbroek, Jef Swerts, Lucía Chávez-Gutiérrez, Giovanni Esposito, Guy Daneels, Eric Karran, Matthew Holt, Kris Gevaert, Diederik W Moechars, Bart De Strooper, and Patrik Verstreken. 2012. “LRRK2 Controls an EndoA Phosphorylation Cycle in Synaptic Endocytosis.” Neuron 75 (6): 1008–1021.
Vancouver
1.
Matta S, Van Kolen K, da Cunha R, van den Bogaart G, Mandemakers W, Miskiewicz K, et al. LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. NEURON. 2012;75(6):1008–21.
IEEE
[1]
S. Matta et al., “LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis,” NEURON, vol. 75, no. 6, pp. 1008–1021, 2012.
@article{3048642,
  abstract     = {LRRK2 is a kinase mutated in Parkinson's disease, but how the protein affects synaptic function remains enigmatic. We identified LRRK2 as a critical regulator of EndophilinA. Using genetic and biochemical studies involving Lrrk loss-of-function mutants and Parkinson-related LRRK2(G2019S) gain-of-kinase function, we show that LRRK2 affects synaptic endocytosis by phosphorylating EndoA at S75, a residue in the BAR domain. We show that LRRK2-mediated EndoA phosphorylation has profound effects on EndoA-dependent membrane tubulation and membrane association in vitro and in vivo and on synaptic vesicle endocytosis at Drosophila neuromuscular junctions in vivo. Our work uncovers a regulatory mechanism that indicates that reduced LRRK2 kinase activity facilitates EndoA membrane association, while increased kinase activity inhibits membrane association. Consequently, both too much and too little LRRK2-dependent EndoA phosphorylation impedes synaptic endocytosis, and we propose a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses.},
  author       = {Matta, Samer and Van Kolen, Kristof and da Cunha, Raquel and van den Bogaart, Geert and Mandemakers, Wim and Miskiewicz, Katarzyna and De Bock, Pieter-Jan and Morais, Vanessa A and Vilain, Sven and Haddad, Dominik and Delbroek, Lore and Swerts, Jef and Chávez-Gutiérrez, Lucía and Esposito, Giovanni and Daneels, Guy and Karran, Eric and Holt, Matthew and Gevaert, Kris and Moechars, Diederik W and De Strooper, Bart and Verstreken, Patrik},
  issn         = {0896-6273},
  journal      = {NEURON},
  keywords     = {BAR DOMAIN,PARKINSONS-DISEASE,VESICLE ENDOCYTOSIS,MEMBRANE CURVATURE,SNARE-PROTEINS,ENDOPHILIN-A,MUTATIONS,FUSION,DEGENERATION,DROSOPHILA NEUROMUSCULAR-JUNCTION},
  language     = {eng},
  number       = {6},
  pages        = {1008--1021},
  title        = {LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis},
  url          = {http://dx.doi.org/10.1016/j.neuron.2012.08.022},
  volume       = {75},
  year         = {2012},
}

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