Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus

作者：Sandeep Kumar Agnihotri, Ruifang Shen, Jihong Li, Xu Gao, Hansruedi Büeler · 发表于：The FASEB Journal · 年份：2017 · DOI：10.1096/fj.201600960rr · 被引用次数：51 · 研究领域：Neurogenesis and neuroplasticity mechanisms、Nuclear Receptors and Signaling、Genetics and Neurodevelopmental Disorders

ABSTRACT 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. Target...