KARS Mutations Impair Brain Myelination by Inducing Oligodendrocyte Deficiency: One Potential Mechanism and Improvement by Melatonin

Author:

Yu Lijia123,Chen Zhilin12,Zhou Xiaolong4,Teng Fei1,Bai Qing‐Ran5,Li Lixi1,Li Yunhong126,Liu Ying127,Zeng Qiyu4,Wang Yong48,Wang Meihua129,Xu Yaling1210,Tang Xiaohui12,Wang Xijin12

Affiliation:

1. Department of Neurology, Shanghai Tongji Hospital, School of Medicine Tongji University Shanghai China

2. Department of Neurology Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China

3. Department of Neurology Shengjing Hospital of China Medical University Shenyang China

4. State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences University of Chinese Academy of Sciences Shanghai China

5. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology Tongji University Shanghai China

6. Department of Neurology First Hospital of Shanxi Medical University Taiyuan China

7. Department of Neurology Huadong Hospital Affiliated to Fudan University Shanghai China

8. School of Life Science and Technology ShanghaiTech University Shanghai China

9. Department of Neurosurgery & Neurocritical Care Huashan Hospital Affiliated to Fudan University Shanghai China

10. National Clinical Research Center for Aging and Medicine, Huashan Hospital Fudan University Shanghai China

Abstract

ABSTRACTIt is very crucial to investigate key molecules that are involved in myelination to gain an understanding of brain development and injury. We have reported for the first time that pathogenic variants p.R477H and p.P505S in KARS, which encodes lysyl‐tRNA synthetase (LysRS), cause leukoencephalopathy with progressive cognitive impairment in humans. The role and action mechanisms of KARS in brain myelination during development are unknown. Here, we first generated Kars knock‐in mouse models through the CRISPR‐Cas9 system. Kars knock‐in mice displayed significant cognitive deficits. These mice also showed significantly reduced myelin density and content, as well as significantly decreased myelin thickness during development. In addition, Kars mutations significantly induced oligodendrocyte differentiation arrest and reduction in the brain white matter of mice. Mechanically, oligodendrocytes’ significantly imbalanced expression of differentiation regulators and increased capase‐3‐mediated apoptosis were observed in the brain white matter of Kars knock‐in mice. Furthermore, Kars mutations significantly reduced the aminoacylation and steady‐state level of mitochondrial tRNALys and decreased the protein expression of subunits of oxidative phosphorylation complexes in the brain white matter. Kars knock‐in mice showed decreased activity of complex IV and significantly reduced ATP production and increased reactive oxygen species in the brain white matter. Significantly increased percentages of abnormal mitochondria and mitochondrion area were observed in the oligodendrocytes of Kars knock‐in mouse brain. Finally, melatonin (a mitochondrion protectant) significantly attenuated mitochondrion and oligodendrocyte deficiency in the brain white matter of KarsR504H/P532S mice. The mice treated with melatonin also showed significantly restored myelination and cognitive function. Our study first establishes Kars knock‐in mammal models of leukoencephalopathy and cognitive impairment and indicates important roles of KARS in the regulation of mitochondria, oligodendrocyte differentiation and survival, and myelination during brain development and application prospects of melatonin in KARS (or even aaRS)related diseases.

Publisher

Wiley

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