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Pumilio1: Understanding a

New Gene Disease

Several years ago, in the course of investigating the post-transcriptional regulation of Ataxin1, I discovered that mutations in the RNA-binding protein Pumilio1 (PUM1) cause a neurodegenerative disease reminiscent of spinocerebellar ataxia type 1 (SCA1). We found that PUM1 negatively regulates ATXN1 levels and is also necessary for normal neurodevelopment. In mice, Pum1 deficiency increases WT Atxn1 mRNA and protein levels by about 40%. Removing a copy of Atxn1 in these mice reduces SCA1-like pathology by normalizing WT Atxn1 levels (Cell, 2015). This led us to propose that PUM1 mutations in humans would also cause disease. As it turned out, loss-of-function mutations of PUM1 underlie two very distinct phenotypes: a late-onset, mild ataxia and a severe neurodevelopmental disorder with cognitive deficits and seizures.  These are both considered forms of SCA47, but for convenience we call the first PRCA (PUM1-related cerebellar ataxia, or SCA47 OMIM #617931) and the second PADDAS (PUM1-associated developmental delay and seizures, OMIM #620719). Although the severity of the PRCA and PADDAS phenotypes tracks with the levels of functional PUM1 (~75% vs. 50% of wild-type levels), precisely what is happening at the molecular level was unclear (Cell, 2018). Especially puzzling was the fact that the mutation that causes the mild disease prevents PUM1 from binding to RNA (therefore it can't bind to its targets), but the severe mutation doesn't disrupte RNA binding.  Yet known PUM1 targets seemed to be upregulated to the same degree in both cases. We hypothesized that PRCA is caused by deregulation of PUM1 targets, but that the more severe and wide-ranging symptoms of PADDAS result from disruption of PUM1’s native interactions with other proteins, along with de-repression of the targets of these complexes. We therefore set out to understand PUM1’s activities in neurons by identifying its native partners using in vivo proteomics. Our findings not only lend support to our hypothesis but demonstrate that, contrary to conventional practice that looks only at an RBP's targets, we need to look at RBP interactions as well (EMBO J, 2023).

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