Loss of Wtap results in cerebellar ataxia and degeneration of Purkinje cells |
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| Affiliation: | 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;2. 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;3. 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;1. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA;2. Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 46556, USA;3. Rush School of Medicine, Chicago, IL 60612, USA;1. Endoscopy Center, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450008, China;2. Department of Gastroenterology, Henan Provincial People''s HospitalZhengzhou, Henan 450008, China |
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| 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. |
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| Keywords: | Wtap METTL3 METTL14 Purkinje cell Ataxia Cerebellum |
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