Casein kinase 1 suppresses activation of REST in insulted hippocampal neurons and halts ischemia-induced neuronal death.
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 REST critical for binding of β-TrCP and targeting of REST for proteasomal degradation. We further 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.
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, New York 10461.
Naoki
N
Kaneko
Jee-Yeon
JY
Hwang
Michael
M
Gertner
Fabrizio
F
Pontarelli
R Suzanne
RS
Zukin
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011774:Pyrvinium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
D047389:Casein Kinase I; D046988:Proteasome Endopeptidase Complex; D011774:Pyrvinium Compounds; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C024631:pyrvinium