Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus
Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus
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DOI：
10.1096/fj.201600960rr
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发表时间：
2017-07-01
期刊：
影响因子：
4.8
通讯作者：
Bueler, Hansruedi
中科院分区：
文献类型：
--
作者：
Agnihotri, Sandeep Kumar;Shen, Ruifang;Bueler, Hansruedi
新的证据表明，线粒体动力学调节成年海马神经发生(ANN)。虽然异常的AHN与抑郁、焦虑和认知功能障碍有关，这些都是包括帕金森病(PD)在内的神经退行性疾病的特征，但以前还没有在神经退行性变的模型中探讨线粒体缺陷对AHN的影响。在这里，我们使用了PTEN诱导的激酶1缺陷(PINK1(-/-))小鼠，这些小鼠缺乏在隐性家族性帕金森病中突变的线粒体激酶。我们发现，线粒体缺陷、糖酵解升高和凋亡增加与培养中PINK1缺陷神经干细胞(NSCs)分化受损但不被取消有关。在PINK1(-/-)小鼠的齿状回，新生的双皮质素阳性神经元呈现异常的树突形态，其成熟程度与野生型小鼠相比有所下降。此外，5-乙炔基-2‘-脱氧尿嘧啶核苷体内标记显示，在PINK1(-/-)小鼠，神经干细胞的增殖数量是正常的，但神经干细胞向双重皮质素阳性神经母细胞和成熟Neun+神经元的分化受阻。最后，我们证明了PINK1(-/-)小鼠的家笼活动和皮质酮水平是正常的，从而排除了体力活动减少和压力增加是神经发生缺陷的原因。我们的结果揭示了在遗传性帕金森病模型中线粒体功能障碍和Ahn受损之间的新的和重要的关系。以线粒体功能和代谢为靶点增加ANN可能为治疗情感障碍和缓解帕金森病和其他神经退行性疾病的相关症状带来希望。Agnihotri，S.K.，沈，R.，Li，J.，Gao，X.，Bileler，H.PINK1的缺失导致成年神经干细胞的代谢缺陷，并阻碍小鼠海马区新生神经元的分化。
Emerging evidence suggests that mitochondrial dynamics regulates adult hippocampal neurogenesis (AHN). Although abnormal AHN has been linked to depression, anxiety, and cognitive dysfunction, which are features of neurodegenerative conditions, including Parkinson's disease (PD), the impact of mitochondrial deficits on AHN have not been explored previously in a model of neurodegeneration. Here, we used PTEN-induced kinase 1-deficient (PINK1(-/-)) mice that lacked a mitochondrial kinase mutated in recessive familial PD. We show that mitochondrial defects, elevated glycolysis, and increased apoptosis are associated with impaired but not abrogated differentiation of PINK1-deficient neural stem cells (NSCs) in culture. In the dentate gyrus of PINK1(-/-) mice, newly generated doublecortin-positive neurons show aberrant dendritic morphology, and their maturation is compromised compared with wild-type mice. In addition, in vivo labeling of NSCs with 5-ethynyl-2'-deoxyuridine shows that proliferating NSC numbers are normal, but the differentiation of NSCs to doublecortin-positive neuroblasts and mature NeuN+ neurons is impeded in PINK1(-/-) mice. Finally, we demonstrate that home cage activity and corticosterone levels of PINK1(-/-) mice are normal, thereby excluding reduced physical activity and increased stress as causes of neurogenesis defects. Our results reveal a new and important relationship between mitochondrial dysfunction and impaired AHN in a genetic PD model. Targeting mitochondrial function and metabolism to increase AHN may hold promise for the treatment of affective disorders and the mitigation of related symptoms in PD and other neurodegenerative conditions. Agnihotri, S. K., Shen, R., Li, J., Gao, X., Bileler, H. Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus.