Sertad1 Plays an Essential Role in Developmental and Pathological Neuron Death

被引:23
作者
Biswas, Subhas C. [2 ,3 ]
Zhang, Yi [1 ]
Iyirhiaro, Grace [1 ]
Willett, Ryan T. [4 ]
Gonzalez, Yasmilde Rodriguez [1 ]
Cregan, Sean P. [5 ,6 ]
Slack, Ruth S. [1 ]
Park, David S. [1 ,7 ]
Greene, Lloyd A. [2 ,3 ]
机构
[1] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5, Canada
[2] Columbia Univ, Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY 10032 USA
[3] Columbia Univ, Coll Phys & Surg, Taub Ctr Alzheimers Dis Res, New York, NY 10032 USA
[4] Columbia Univ, Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA
[5] Univ Western Ontario, Robarts Res Inst, London, ON N6A 5K8, Canada
[6] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 5K8, Canada
[7] Pusan Natl Univ, Dept Cogno Mechatron Engn, Pusan 609735, South Korea
基金
新加坡国家研究基金会;
关键词
CYCLIN-DEPENDENT KINASES; NERVE GROWTH-FACTOR; CELL-CYCLE; DNA-DAMAGE; SYMPATHETIC NEURONS; ALZHEIMERS-DISEASE; PC12; CELLS; AMYLOIDOGENIC ROUTE; PROTEIN P34(SEI-1); CORTICAL-NEURONS;
D O I
10.1523/JNEUROSCI.6421-09.2010
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 A beta (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 ofDNAdamage and Alzheimer's disease. It may therefore be a suitable target for therapeutic intervention.
引用
收藏
页码:3973 / 3982
页数:10
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