Sertad1 plays an essential role in developmental and pathological neuron death.
Developmental and pathological death of neurons requires activation of a defined pathway of cell cycle proteins. However, it is unclear how this pathway is regulated and whether it is relevant in vivo. A screen for transcripts robustly induced in cultured neurons by DNA damage identified Sertad1, a Cdk4 (cyclin-dependent kinase 4) activator. Sertad1 is also induced in neurons by nerve growth factor (NGF) deprivation and Abeta (beta-amyloid). RNA interference-mediated downregulation of Sertad1 protects neurons in all three death models. Studies of NGF withdrawal indicate that Sertad1 is required to initiate the apoptotic cell cycle pathway since its knockdown blocks subsequent pathway events. Finally, we find that Sertad1 expression is required for developmental neuronal death in the cerebral cortex. Sertad1 thus appears to be essential for neuron death in trophic support deprivation in vitro and in vivo and in models of DNA damage and Alzheimer's disease. It may therefore be a suitable target for therapeutic intervention.
Department of Pathology and Cell Biology and Taub Center for Alzheimer's Disease Research, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Subhas C
SC
Biswas
Yi
Y
Zhang
Grace
G
Iyirhiaro
Ryan T
RT
Willett
Yasmilde
Y
Rodriguez Gonzalez
Sean P
SP
Cregan
Ruth S
RS
Slack
David S
DS
Park
Lloyd A
LA
Greene
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000201:enzymology / Q000473:pathology* / Q000502:physiology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016716:PC12 Cells; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D000092468:Bromodomain Containing Proteins
D051017:Apoptosis Regulatory Proteins; D051358:Cyclin-Dependent Kinase 4; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C485730:Sertad1 protein, mouse; D000092468:Bromodomain Containing Proteins