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LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism

Amaia M Arranz, Lore Delbroek, Kristof Van Kolen, Marco R Guimarães, Wim Mandemakers, Guy Daneels, Samer Matta, Sara Calafate, Hamdy Shaban, Pieter Baatsen, et al.
(2015) JOURNAL OF CELL SCIENCE. 128(3). p.541-552
Author
Organization
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, but the precise physiological function of the protein remains ill-defined. Recently, our group proposed a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses in the Drosophila melanogaster neuromuscular junctions. Flies harbor only one Lrrk gene, which might encompass the functions of both mammalian LRRK1 and LRRK2. We therefore studied the role of LRRK2 in mammalian synaptic function and provide evidence that knockout or pharmacological inhibition of LRRK2 results in defects in synaptic vesicle endocytosis, altered synaptic morphology and impairments in neurotransmission. In addition, our data indicate that mammalian endophilin A1 (EndoA1, also known as SH3GL2) is phosphorylated by LRRK2 in vitro at T73 and S75, two residues in the BAR domain. Hence, our results indicate that LRRK2 kinase activity has an important role in the regulation of clathrin-mediated endocytosis of synaptic vesicles and subsequent neurotransmission at the synapse.
Keywords
DOMAIN, PARKINSONS-DISEASE, DYNAMIN, ENDOPHILIN, KNOCKOUT MICE, ALPHA-SYNUCLEIN, MEMBRANE CURVATURE, HIPPOCAMPAL SYNAPSES, CENTRAL-NERVOUS-SYSTEM, Endocytosis, CLATHRIN-MEDIATED ENDOCYTOSIS, Endophilin A1, LRRK2

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MLA
Arranz, Amaia M., et al. “LRRK2 Functions in Synaptic Vesicle Endocytosis through a Kinase-Dependent Mechanism.” JOURNAL OF CELL SCIENCE, vol. 128, no. 3, 2015, pp. 541–52, doi:10.1242/jcs.158196.
APA
Arranz, A. M., Delbroek, L., Van Kolen, K., Guimarães, M. R., Mandemakers, W., Daneels, G., … Moechars, D. (2015). LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism. JOURNAL OF CELL SCIENCE, 128(3), 541–552. https://doi.org/10.1242/jcs.158196
Chicago author-date
Arranz, Amaia M, Lore Delbroek, Kristof Van Kolen, Marco R Guimarães, Wim Mandemakers, Guy Daneels, Samer Matta, et al. 2015. “LRRK2 Functions in Synaptic Vesicle Endocytosis through a Kinase-Dependent Mechanism.” JOURNAL OF CELL SCIENCE 128 (3): 541–52. https://doi.org/10.1242/jcs.158196.
Chicago author-date (all authors)
Arranz, Amaia M, Lore Delbroek, Kristof Van Kolen, Marco R Guimarães, Wim Mandemakers, Guy Daneels, Samer Matta, Sara Calafate, Hamdy Shaban, Pieter Baatsen, Pieter-Jan De Bock, Kris Gevaert, Pieter Vanden Berghe, Patrik Verstreken, Bart De Strooper, and Diederik Moechars. 2015. “LRRK2 Functions in Synaptic Vesicle Endocytosis through a Kinase-Dependent Mechanism.” JOURNAL OF CELL SCIENCE 128 (3): 541–552. doi:10.1242/jcs.158196.
Vancouver
1.
Arranz AM, Delbroek L, Van Kolen K, Guimarães MR, Mandemakers W, Daneels G, et al. LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism. JOURNAL OF CELL SCIENCE. 2015;128(3):541–52.
IEEE
[1]
A. M. Arranz et al., “LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism,” JOURNAL OF CELL SCIENCE, vol. 128, no. 3, pp. 541–552, 2015.
@article{5928583,
  abstract     = {{Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, but the precise physiological function of the protein remains ill-defined. Recently, our group proposed a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses in the Drosophila melanogaster neuromuscular junctions. Flies harbor only one Lrrk gene, which might encompass the functions of both mammalian LRRK1 and LRRK2. We therefore studied the role of LRRK2 in mammalian synaptic function and provide evidence that knockout or pharmacological inhibition of LRRK2 results in defects in synaptic vesicle endocytosis, altered synaptic morphology and impairments in neurotransmission. In addition, our data indicate that mammalian endophilin A1 (EndoA1, also known as SH3GL2) is phosphorylated by LRRK2 in vitro at T73 and S75, two residues in the BAR domain. Hence, our results indicate that LRRK2 kinase activity has an important role in the regulation of clathrin-mediated endocytosis of synaptic vesicles and subsequent neurotransmission at the synapse.}},
  author       = {{Arranz, Amaia M and Delbroek, Lore and Van Kolen, Kristof and Guimarães, Marco R and Mandemakers, Wim and Daneels, Guy and Matta, Samer and Calafate, Sara and Shaban, Hamdy and Baatsen, Pieter and De Bock, Pieter-Jan and Gevaert, Kris and Vanden Berghe, Pieter and Verstreken, Patrik and De Strooper, Bart and Moechars, Diederik}},
  issn         = {{0021-9533}},
  journal      = {{JOURNAL OF CELL SCIENCE}},
  keywords     = {{DOMAIN,PARKINSONS-DISEASE,DYNAMIN,ENDOPHILIN,KNOCKOUT MICE,ALPHA-SYNUCLEIN,MEMBRANE CURVATURE,HIPPOCAMPAL SYNAPSES,CENTRAL-NERVOUS-SYSTEM,Endocytosis,CLATHRIN-MEDIATED ENDOCYTOSIS,Endophilin A1,LRRK2}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{541--552}},
  title        = {{LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism}},
  url          = {{http://doi.org/10.1242/jcs.158196}},
  volume       = {{128}},
  year         = {{2015}},
}
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