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Regulation of neuronal mRNA splicing and Tau isoform ratio by ATXN3 through deubiquitylation of splicing factors

By Andreia Neves-Carvalho, Sara Duarte-Silva, Joana Silva, Bruno Almeida, Sasja Heetveld, Ioannis Sotiropoulos, Peter Heutink, Ka Wan Li, PatrĂ­cia Maciel

Posted 23 Jul 2019
bioRxiv DOI: 10.1101/711424

The ubiquitylation/deubiquitylation balance in cells is maintained by Deubiquitylating enzymes, including ATXN3. The precise role of this protein, mutated in SCA3, remains elusive, as few substrates for its deubiquitylating activity were identified. Therefore, we characterized the ubiquitome of neuronal cells lacking ATXN3, and found altered polyubiquitylation in a large proportion of proteins involved in RNA metabolism, including splicing factors. Using transcriptomic analysis and reporter minigenes we confirmed that splicing was globally altered in these cells. Among the targets with altered splicing was SRSF7 (9G8), a key regulator of MAPT (Tau) exon 10 splicing. Loss-of-function of ATXN3 led to a deregulation of MAPT exon 10 splicing resulting in a decreased 4R/3R-Tau ratio. Similar alterations were found in the brain of a SCA3 mouse and humans, pointing to a relevant role of this mechanism in SCA3, and establishing a previously unsuspected link between two key proteins involved in different neurodegenerative disorders.

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