DOI: 10.1002/ame2.12318
A neuron-specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes
Hanxuan Sheng1
Dan Lu2
Xiaolong Qi2
Yahao Ling1
Jing Li2
Xu Zhang2
Wei Dong1
Wei Chen1
Shan Gao2
Xiang Gao2
Li Zhang2
Lianfeng Zhang1
1.Key Laboratory of Human Disease Comparative Medicine,National Health Commission of China(NHC),Institute of Laboratory Animal Science,Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing,China2.Beijing Engineering Research Center for Experimental Animal Models of Human Diseases,Institute of Laboratory Animal Science,Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing,China
摘要：Background:Multiple mitochondrial dysfunction syndromes(MMDS)are rare mito-chondrial diseases caused by mutation of mitochondrial iron-sulfur cluster synthesis proteins.This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death.Methods:We generated neuron-specific Isca1 knockout rat(Isca1flox/flox-NeuN-Cre)using CRISPR-Cas9 technology.The brain structure changes of CKO rats were stud-ied with MRI,and the behavior abnormalities were analyzed through gait analysis and open field tests,Y maze tests and food maze tests.The pathological changes of neurons were analyzed through H&E staining,Nissl staining,and Golgi staining.Mitochondrial damage was assessed by TEM,western blot and ATP assay,and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons.Results:This study established the disease model of MMDS5 in the nervous system for the first time,and found that after Isca1 loss,the rats suffered from developmental retardation,epilepsy,memory impairment,massive neuronal death,reduced number of Nissl bodies and dendritic spines,mitochondrial fragmentation,cristae fracture,re-duced content of respiratory chain complex protein,and reduced production of ATP.Isca1 knockout caused neuronal oncosis.Conclusions:This rat model can be used to study the pathogenesis of MMDS.In addi-tion,compared with human MMDS5,the rat model can survive up to 8weeks of age,effectively extending the window of clinical treatment research,and can be used for the treatment of neurological symptoms in other mitochondrial diseases.
机标关键词：knockoutisca1developmentsdysfunctionmitochondrialmultipleneuron-specificsyndromes
论文发表日期：2023-04-28
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：13( 155-167 )
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