英国科学家发现,老鼠大脑内缺乏ATP1A3基因可能引发严重的癫痫症状。该研究结果发表在最新一期的《美国国家科学院院刊》上。
有些人会因为头部受到重创、脑部肿瘤、其他神经疾病等而引发癫痫。科学家一直认为,大部分癫痫可能由基因引起,但一直未能获得证实。
英国利兹大学的神经学家斯蒂芬·克拉克特领导的研究团队将正常老鼠与患有癫痫的老鼠进行杂交,并通过基因工程的方法让正常老鼠拥有额外的ATP1A3基因的复制。额外的复制弥补了ATP1A3基因的缺乏,因此,其后代没有癫痫症状,其平衡钠和钾浓度的酶也处于正常状态。
研究人员称,在老鼠和人类中,ATP1A3基因都负责调节大脑中钠和钾的浓度。ATP1A3基因产生一种酶,该酶就像钠钾泵一样,可以调节大脑中钠和钾的浓度。患上了癫痫的老鼠缺乏ATP1A3基因,生成的酶不活跃,不足以平衡钠和钾的浓度,因此,老鼠的癫痫会定期发作。
研究人员筛查了许多癫痫病人的DNA样本,以证实是否同样的基因缺陷使一些人更容易患上癫痫,他们称,人类和老鼠基因99%的匹配度意味着该基因可能在人体内也起作用。
研究人员指出,在癫痫病患者中,大脑处于高度兴奋状态,这意味着,当癫痫病人的大脑遭受刺激时,会更容易出现神经元放电的情况,让癫痫症状更加明显,钠和钾影响着神经元放电活动。
科学家表示,如果该研究能应用于人类,将有助于找到治疗癫痫的全新方法。一种方法是给病人提供人工合成的钠钾泵酶来帮助调解大脑中钠和钾的浓度;也可以设计药物来激活这个不再活跃的酶。(生物谷Bioon.com)
生物谷推荐原始出处:
PNAS August 3, 2009, doi: 10.1073/pnas.0904817106
Mutation I810N in the α3 isoform of Na+,K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS
Steven J. Clapcotea,b,1, Steven Duffya, Gang Xiea, Greer Kirshenbauma,c, Allison R. Becharda, Vivien Rodacker Schackd, Janne Petersend, Laleh Sinaia,c, Bechara J. Saaba,c, Jason P. Lerche, Berge A. Minassianc,e, Cameron A. Ackerleye, John G. Sledc,e, Miguel A. Cortezc,e, Jeffrey T. Hendersonc, Bente Vilsend and John C. Rodera,c
aSamuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5;
bInstitute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, United Kingdom;
cDepartments of Medical Biophysics, Medical Genetics, Paediatrics, and Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada M5S 1A1;
dDepartment of Physiology and Biophysics, Centre for Membrane Pumps in Cells and Disease–PUMPKIN, Danish National Research Foundation, University of Aarhus, DK-8000 Aarhus, Denmark; and
eMouse Imaging Centre, Program in Genetics and Genome Biology, and Divisions of Neurology and Pathology, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8
In a mouse mutagenesis screen, we isolated a mutant, Myshkin (Myk), with autosomal dominant complex partial and secondarily generalized seizures, a greatly reduced threshold for hippocampal seizures in vitro, posttetanic hyperexcitability of the CA3-CA1 hippocampal pathway, and neuronal degeneration in the hippocampus. Positional cloning and functional analysis revealed that Myk/+ mice carry a mutation (I810N) which renders the normally expressed Na+,K+-ATPase α3 isoform inactive. Total Na+,K+-ATPase activity was reduced by 42% in Myk/+ brain. The epilepsy in Myk/+ mice and in vitro hyperexcitability could be prevented by delivery of additional copies of wild-type Na+,K+-ATPase α3 by transgenesis, which also rescued Na+,K+-ATPase activity. Our findings reveal the functional significance of the Na+,K+-ATPase α3 isoform in the control of epileptiform activity and seizure behavior.