title: Parkin regulates kainate receptors by interacting with the GluK2 subunit.
abstract: Although loss-of-function mutations in the PARK2 gene, the gene that encodes the protein parkin, cause autosomal recessive juvenile parkinsonism, the responsible molecular mechanisms remain unclear. Evidence suggests that a loss of parkin dysregulates excitatory synapses. Here we show that parkin interacts with the kainate receptor (KAR) GluK2 subunit and regulates KAR function. Loss of parkin function in primary cultured neurons causes GluK2 protein to accumulate in the plasma membrane, potentiates KAR currents and increases KAR-dependent excitotoxicity. Expression in the mouse brain of a parkin mutant causing autosomal recessive juvenile parkinsonism results in GluK2 protein accumulation and excitotoxicity. These findings show that parkin regulates KAR function in vitro and in vivo, and suggest that KAR upregulation may have a pathogenetic role in parkin-related autosomal recessive juvenile parkinsonism.
authors.affiliation: IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Cusano Milanino, 20095 Milan, Italy.
authors.forename: AnnaMaria
authors.initials: A
authors.lastname: Maraschi
authors.affiliation: IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Cusano Milanino, 20095 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciammola
authors.affiliation: CNR Institute of Neuroscience, Department of BIOMETRA, University of Milan, 20129 Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Folci
authors.affiliation: IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Cusano Milanino, 20095 Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sassone
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ronzitti
authors.affiliation: Department of Biosciences, Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Graziella
authors.initials: G
authors.lastname: Cappelletti
authors.affiliation: 1] IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Cusano Milanino, 20095 Milan, Italy [2] 'Dino Ferrari' Center, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, 113-8421 Tokyo, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, 113-8421 Tokyo, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Department of Biosciences, Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Mazzanti
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
authors.forename: Evelina
authors.initials: E
authors.lastname: Chieregatti
authors.affiliation: Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, University of Bordeaux, 33000 Bordeaux, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mulle
authors.affiliation: CNR Institute of Neuroscience, Department of BIOMETRA, University of Milan, 20129 Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
authors.affiliation: IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Cusano Milanino, 20095 Milan, Italy.
authors.forename: Jenny
authors.initials: J
authors.lastname: Sassone
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000097806:GluK2 Kainate Receptor
chemical_list: D018092:Kainic Acid Receptors; D044767:Ubiquitin-Protein Ligases; D000097806:GluK2 Kainate Receptor; C111567:parkin protein