Parkin regulates kainate receptors by interacting with the GluK2 subunit

AnnaMaria Maraschi, Andrea Ciammola, Alessandra Folci, Francesca Sassone, Giuseppe Ronzitti, Graziella Cappelletti, Vincenzo Silani, Shigeto Sato, Nobutaka Hattori, Michele Mazzanti, Evelina Chieregatti, Christophe Mulle, Maria Passafaro and Jenny Sassone ()
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AnnaMaria Maraschi: IRCCS Istituto Auxologico Italiano
Andrea Ciammola: IRCCS Istituto Auxologico Italiano
Alessandra Folci: CNR Institute of Neuroscience, University of Milan
Francesca Sassone: IRCCS Istituto Auxologico Italiano
Giuseppe Ronzitti: Istituto Italiano di Tecnologia
Graziella Cappelletti: Università degli Studi di Milano
Vincenzo Silani: IRCCS Istituto Auxologico Italiano
Shigeto Sato: Juntendo University School of Medicine
Nobutaka Hattori: Juntendo University School of Medicine
Michele Mazzanti: Università degli Studi di Milano
Evelina Chieregatti: Istituto Italiano di Tecnologia
Christophe Mulle: Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, University of Bordeaux
Maria Passafaro: CNR Institute of Neuroscience, University of Milan
Jenny Sassone: IRCCS Istituto Auxologico Italiano

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6182

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