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, and we have found that in humans, PUM1 mutations actually cause two distinct diseases, one neurodevelopmental, and one neurodegenerative (Cell, 2018). Ongoing work in the lab seeks to understand the pathogenesis of these diseases by applying genetic and neuroscientific tools to mouse models.

For more clinical details please see Human Disease Genes Website Series: http://humandiseasegenes.nl/pum1/