Loss of Wtap results in cerebellar ataxia and degeneration of Purkinje cells

doi:10.1016/j.jgg.2022.03.001

. 2022 Sep;49(9):847-858.

doi: 10.1016/j.jgg.2022.03.001. Epub 2022 Mar 15.

Loss of Wtap results in cerebellar ataxia and degeneration of Purkinje cells

Yeming Yang¹, Guo Huang¹, Xiaoyan Jiang², Xiao Li², Kuanxiang Sun², Yi Shi¹, Zhenglin Yang³, Xianjun Zhu⁴

Affiliations

¹ The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China.
² The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.
³ The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China. Electronic address: zliny@yahoo.com.
⁴ The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China; Key Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining, Qinghai 810008, China. Electronic address: xjzhu@uestc.edu.cn.

PMID: 35304325
DOI: 10.1016/j.jgg.2022.03.001

Loss of Wtap results in cerebellar ataxia and degeneration of Purkinje cells

Yeming Yang et al. J Genet Genomics. 2022 Sep.

. 2022 Sep;49(9):847-858.

doi: 10.1016/j.jgg.2022.03.001. Epub 2022 Mar 15.

Authors

Yeming Yang¹, Guo Huang¹, Xiaoyan Jiang², Xiao Li², Kuanxiang Sun², Yi Shi¹, Zhenglin Yang³, Xianjun Zhu⁴

Affiliations

¹ The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China.
² The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.
³ The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China. Electronic address: zliny@yahoo.com.
⁴ The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China; Key Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining, Qinghai 810008, China. Electronic address: xjzhu@uestc.edu.cn.

PMID: 35304325
DOI: 10.1016/j.jgg.2022.03.001

Abstract

N⁶-methyladenosine (m⁶A) modification, which is achieved by the METTL3/METTL14/WTAP methyltransferase complex, is the most abundant internal mRNA modification. Although recent evidence indicates that m⁶A can regulate neurodevelopment as well as synaptic function, the roles of m⁶A modification in the cerebellum and related synaptic connections are not well established. Here, we report that Purkinje cell (PC)-specific WTAP knockout mice display early-onset ataxia concomitant with cerebellar atrophy due to extensive PC degeneration and apoptotic cell death. Loss of Wtap also causes the aberrant degradation of multiple PC synapses. WTAP depletion leads to decreased expression levels of METTL3/14 and reduced m⁶A methylation in PCs. Moreover, the expression of GFAP and NF-L in the degenerating cerebellum is increased, suggesting severe neuronal injuries. In conclusion, this study demonstrates the critical role of WTAP-mediated m⁶A modification in cerebellar PCs, thus providing unique insights related to neurodegenerative disorders.

Keywords: Ataxia; Cerebellum; METTL14; METTL3; N(6)-methyladenosine; Purkinje cell; Wtap.

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Conflict of interest statement

Conflict of interest All authors declare that there are no competing interests.

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Loss of Wtap results in cerebellar ataxia and degeneration of Purkinje cells

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Loss of Wtap results in cerebellar ataxia and degeneration of Purkinje cells

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