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

N-6-methyladenosine (m(6)A) modification, which is achieved by the METTL3/METTL14/WTAP methyl-transferase complex, is the most abundant internal mRNA modification. Although recent evidence indicates that m(6)A can regulate neurodevelopment as well as synaptic function, the roles of m(6)A 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 m(6)A 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 m(6)A modification in cerebellar PCs, thus providing unique insights related to neurodegenerative disorders. Copyright (C) 2022, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.

Automated summary

The study reveals the critical role of WTAP-mediated m(6)A modification in cerebellar Purkinje cells, which regulates the degradation of multiple cell synapses and affects cerebellar development and function. Loss of WTAP leads to early-onset ataxia, cerebellar atrophy, and severe neuronal injuries.