BioProject

We performed an shRNA screen to identify novel ATXN1 protein level regulators in hope of finding some that may improve brainstem function in SCA1. More...

We performed an shRNA screen to identify novel ATXN1 protein level regulators in hope of finding some that may improve brainstem function in SCA1. We found that two closely related BTB-ZF transcription factors, ZBTB7A and ZBTB7B, positively regulate ATXN1 levels in vitro and in vivo, with ZBTB7B displaying a more pronounced effect. ZBTB7B regulates ATXN1 by regulating the transcription of RSK3 (RPS6KA2). RSK3 in turn regulates ATXN1 by phosphorylating its serine 776 (S776), a residue critical for ATXN1 stability, which is similar to another one previously identified ATXN1 kinase, MSK1. However, despite the convergent function of the two kinases, each kinase selectively regulates Atxn1 in a brain region-dependent manner; Msk1 predominantly regulates Atxn1 in the cerebellum, while Rsk3 is the predominant regulator of Atxn1 in the brainstem. Our results demonstrate that toxic protein levels can be modulated by different regulators in select brain regions, and hence targeting multiple regulators can expand therapeutic efficacy to rescue multiple degenerating brain areas. Overall design: mRNA profiles of Daoy (human brain cancer) cells overexpressing either wild-type ZBTB7B or zinc-finger domain mutant (R363L) ZBTB7B. Less...