RT Journal Article
SR Electronic
T1 Dosage sensitivity in Pumilio1-associated diseases involves two distinct mechanisms
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.11.435015
DO 10.1101/2021.03.11.435015
A1 Salvatore Botta
A1 Nicola de Prisco
A1 Alexei Chemiakine
A1 Maximilian Cabaj
A1 Purvi Patel
A1 Rajesh K. Soni
A1 Vincenzo A. Gennarino
YR 2021
UL http://biorxiv.org/content/early/2021/11/23/2021.03.11.435015.abstract
AB Mutations in the RNA-binding protein (RBP) Pumilio1 (PUM1) can cause dramatically different phenotypes. Mild mutations that reduce PUM1 levels by 25% lead to a mild, adult-onset ataxia, whereas more severe mutations that reduce PUM1 levels 40-60% produce an infantile syndrome involving multiple developmental delays and seizures. Why this difference in expression should cause such different phenotypes has been unclear; known PUM1 targets are de-repressed to equal degrees in both diseases. We therefore sought to identify PUM1’s protein partners in the murine brain. We identified a number of putative interactors involved in different aspects of RNA metabolism such as silencing, alternative splicing, and polyadenylation. We find that PUM1 haploinsufficiency alters the stability of several interactors and disrupts the regulation of targets of those interactors, whereas mild PUM1 loss only de-represses PUM1-specific targets. We validated these phenomena in patient-derived cell lines and show that normalizing PUM1 levels rescues the levels of interactors and their targets. We therefore propose that dosage sensitivity does not necessarily reflect a linear change in levels but can involve distinct mechanisms. Studying the interactors of RBPs in vivo will be necessary to understand their functions in neurological diseases.Competing Interest StatementThe authors have declared no competing interest.