Casein Kinase 1 suppresses activation of REST in insulted hippocampal neurons and halts ischemia-induced neuronal death

Naoki Kaneko, Jee Yeon Hwang, Michael Gertner, Fabrizio Pontarelli, R. Suzanne Zukin

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Repressor Element-1 (RE1) Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF) is a gene-silencing factor that is widely expressed during embryogenesis and plays a strategic role in neuronal differentiation. Recent studies indicate that REST can be activated in differentiated neurons during a critical window of time in postnatal development and in adult neurons in response to neuronal insults such as seizures and ischemia. However, the mechanism by which REST is regulated in neurons is as yet unknown. Here, we show that REST is controlled at the level of protein stability via β-TrCP-dependent, ubiquitin-based proteasomal degradation in differentiated neurons under physiological conditions and identify Casein Kinase 1 (CK1) as an upstream effector that bidirectionally regulates REST cellular abundance. CK1 associates with and phosphorylates REST at two neighboring, but distinct, motifs within the C terminus of RESTcritical for binding of β-TrCP and targeting of REST for proteasomal degradation.Wefurther show that global ischemia in rats in vivo triggers a decrease in CK1 and an increase in REST in selectively vulnerable hippocampal CA1 neurons. Administration of the CK1 activator pyrvinium pamoate by in vivo injection immediately after ischemia restores CK1 activity, suppresses REST expression, and rescues neurons destined to die. Our results identify a novel and previously unappreciated role for CK1 as a brake on REST stability and abundance in adult neurons and reveal that loss of CK1 is causally related to ischemia-induced neuronal death. These findings point to CK1 as a potential therapeutic target for the amelioration of hippocampal injury and cognitive deficits associated with global ischemia.

Original languageEnglish (US)
Pages (from-to)6030-6039
Number of pages10
JournalJournal of Neuroscience
Volume34
Issue number17
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Neuroscience(all)

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