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Leucine-rich repeat kinase 2 phosphorylation on synapsin I regulates glutamate release at pre-synaptic sites.
Marte, Antonella; Russo, Isabella; Rebosio, Claudia; Valente, Pierluigi; Belluzzi, Elisa; Pischedda, Francesca; Montani, Caterina; Lavarello, Chiara; Petretto, Andrea; Fedele, Ernesto; Baldelli, Pietro; Benfenati, Fabio; Piccoli, Giovanni; Greggio, Elisa; Onofri, Franco.
Afiliación
  • Marte A; Department of Experimental Medicine, University of Genova, Genova, Italy.
  • Russo I; Department of Biology, University of Padova, Padova, Italy.
  • Rebosio C; Department of Pharmacy, University of Genova, Genova, Italy.
  • Valente P; Department of Experimental Medicine, University of Genova, Genova, Italy.
  • Belluzzi E; IRCCS Ospedale Policlinico San Martino, Genova, Italy.
  • Pischedda F; Rheumatology Unit, Department of Medicine-DIMED, University Hospital of Padova, Padova, Italy.
  • Montani C; Center for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
  • Lavarello C; Dulbecco Telethon Institute, Trento, Italy.
  • Petretto A; Center for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
  • Fedele E; Dulbecco Telethon Institute, Trento, Italy.
  • Baldelli P; Laboratory of Mass Spectrometry - Core Facilities, Istituto Giannina Gaslini, Genova, Italy.
  • Benfenati F; Laboratory of Mass Spectrometry - Core Facilities, Istituto Giannina Gaslini, Genova, Italy.
  • Piccoli G; Department of Pharmacy, University of Genova, Genova, Italy.
  • Greggio E; IRCCS Ospedale Policlinico San Martino, Genova, Italy.
  • Onofri F; Department of Experimental Medicine, University of Genova, Genova, Italy.
J Neurochem ; 150(3): 264-281, 2019 08.
Article en En | MEDLINE | ID: mdl-31148170
Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain scaffolding protein with kinase and GTPase activities involved in synaptic vesicle (SV) dynamics. While its role in Parkinson's disease has been largely investigated, little is known about LRRK2 physiological role and until now few proteins have been described as substrates. We have previously demonstrated that LRRK2 through its WD40 domain interacts with synapsin I, an important SV-associated phosphoprotein involved in neuronal development and in the regulation of neurotransmitter release. To test whether synapsin I is substrate for LRRK2 and characterize the properties of its phosphorylation, we used in vitro kinase and binding assays as well as cellular model and site-direct mutagenesis. Using synaptosomes in superfusion, patch-clamp recordings in autaptic WT and synapsin I KO cortical neurons and SypHy assay on primary cortical culture from wild-type and BAC human LRRK2 G2019S mice we characterized the role of LRRK2 kinase activity on glutamate release and SV trafficking. Here we reported that synapsin I is phosphorylated by LRRK2 and demonstrated that the interaction between LRRK2 WD40 domain and synapsin I is crucial for this phosphorylation. Moreover, we showed that LRRK2 phosphorylation of synapsin I at threonine 337 and 339 significantly reduces synapsin I-SV/actin interactions. Using complementary experimental approaches, we demonstrated that LRRK2 controls glutamate release and SV dynamics in a kinase activity and synapsin I-dependent manner. Our findings show that synapsin I is a LRRK2 substrate and describe a novel mechanisms of regulation of glutamate release by LRRK2 kinase activity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sinapsinas / Transmisión Sináptica / Ácido Glutámico / Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Neurochem Año: 2019 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sinapsinas / Transmisión Sináptica / Ácido Glutámico / Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Neurochem Año: 2019 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido