Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus.
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 ofPINK1-/-mice, newly generated doublecortin-positive neurons show aberrant dendritic morphology, and their maturation is compromised compared with wild-type mice. In addition,in vivolabeling 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 inPINK1-/-mice. Finally, we demonstrate that home cage activity and corticosterone levels ofPINK1-/-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., Büeler, H. Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus.
School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
Sandeep Kumar
SK
Agnihotri
School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
Ruifang
R
Shen
Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
Jihong
J
Li
Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
Xu
X
Gao
School of Life Science and Technology, Harbin Institute of Technology, Harbin, China; hbueler@hit.edu.cn.
Hansruedi
H
Büeler
D000818:Animals; D001522:Behavior, Animal; D002454:Cell Differentiation; D003345:Corticosterone / Q000097:blood; D005260:Female; D005838:Genotype; D006019:Glycolysis / Q000502:physiology; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099202:PTEN-Induced Putative Kinase
D003345:Corticosterone; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase
PTEN-induced kinase; Parkinson’s disease; adult neurogenesis; mitochondria