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.

Parkin regulates kainate receptors by interacting with the GluK2 subunit / A. Maraschi, A. Ciammola, A. Folci, F. Sassone, G. Ronzitti, G. Cappelletti, V. Silani, S. Sato, N. Hattori, M. Mazzanti, E. Chieregatti, C. Mulle, M. Passafaro, J. Sassone. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 5(2014), pp. 5182.1-5182.10. [10.1038/ncomms6182]

Parkin regulates kainate receptors by interacting with the GluK2 subunit

A. Folci;F. Sassone
;
G. Cappelletti;V. Silani;M. Mazzanti;
2014

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.
recessive juvenile parkinsonism; ubiquitin-protein ligase; substantia-nigra; squirrel-monkey; alpha-synuclein; human-brain; disease; trafficking; gene; excitotoxicity
Settore MED/26 - Neurologia
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
Settore BIO/18 - Genetica
2014
Article (author)
File in questo prodotto:
File Dimensione Formato  
Maraschi A Nature 2014.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 1.85 MB
Formato Adobe PDF
1.85 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/242621
Citazioni
  • ???jsp.display-item.citation.pmc??? 23
  • Scopus 36
  • ???jsp.display-item.citation.isi??? 35
social impact