Loss of <i>Wtap</i> results in cerebellar ataxia and degeneration of Purkinje cells

Yeming Yang; Guo Huang; Xiaoyan Jiang; Xiao Li; Kuanxiang Sun; Yi Shi; Zhenglin Yang; Xianjun Zhu

doi:10.1016/j.jgg.2022.03.001

Volume 49 Issue 9

Sep. 2022

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Article Navigation > Journal of Genetics and Genomics > 2022 > 49(9): 847-858

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

doi: 10.1016/j.jgg.2022.03.001

a. 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;
b. 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;
c. 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

Funds:

This study was supported by the National Natural Science Foundation of China (82121003, 81970841, and 81790643), the Department of Science and Technology of Sichuan Province (2021YFS0386, 2021YFS0369, 20ZYD038, 20ZYD037, 2020JDZH0026, 2021JDZH0022), the CAMS Innovation Fund for Medical Sciences (2019–12M-5-032), Huanhua Distingished Scholar grant, and the Department of Chengdu Science and Technology (2021-YF05-01316-SN). The funders had no role in the study design, data collection and analysis, or preparation of the manuscript. The authors would like to thank Chengdu LiLai Biotechnology Co., Ltd., for technical assistance with histology analysis.

Received Date: 2021-12-06
Accepted Date: 2022-03-04
Rev Recd Date: 2022-03-03
Publish Date: 2022-03-15

Abstract

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.
- N⁶-methyladenosine,
- Wtap,
- METTL3,
- METTL14,
- Purkinje cell,
- Ataxia,
- Cerebellum

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References(36)

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