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A more recent version of this article appeared on August 1, 2007
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Submitted on November 8, 2005
Revised on May 22, 2007
Accepted on May 25, 2007
*Centre for Neuronal Survival and Cell Biology of Excitable Tissues, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada; Institut National de la Santé et de la Recherche Médicale U 679, Groupe Hospitalier Pitié-Salpêtrière, 75651 Paris Cedex 13, France
Monitoring Editor: Ben Margolis
Mutations in the parkin gene result in an autosomal recessive juvenile-onset form of Parkinson’s disease. As an E3 ubiquitin-ligase, parkin promotes the attachment of ubiquitin onto specific substrate proteins. Defects in the ubiquitination of parkin substrates are therefore believed to lead to neurodegeneration in Parkinson’s disease. Here, we identify the PDZ protein PICK1 as a novel parkin substrate. We find that parkin binds PICK1 via a PDZ-mediated interaction, which predominantly promotes PICK1 monoubiquitination rather than polyubiquitination. Consistent with monoubiquitination and recent work implicating parkin in proteasome-independent pathways, parkin does not promote PICK1 degradation. However, parkin regulates the effects of PICK1 on one of its other PDZ partners, the acid-sensing ion channel (ASIC). Overexpression of wild-type, but not PDZ binding- or E3 ubiquitin-ligase-defective parkin abolishes the previously described, protein kinase C-induced, PICK1-dependent potentiation of ASIC2a currents in nonneuronal cells. Conversely, the loss of parkin in hippocampal neurons from parkin knockout mice unmasks prominent potentiation of native ASIC currents, which is normally suppressed by endogenous parkin in wild-type neurons. Given that ASIC channels contribute to excitotoxicity, our work provides a mechanism explaining how defects in parkin-mediated PICK1 monoubiquitination could enhance ASIC activity and thereby promote neurodegeneration in Parkinson’s disease.
These authors contributed equally to this work.
Address correspondence to:
Philippe Séguéla (philippe.seguela{at}mcgill.ca) or Edward A. Fon (ted.fon{at}mcgill.ca)
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