Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative proteinopathy, in which a mutant protein (in this case, ATAXIN1) accumulates in neurons and exerts toxicity; in SCA1, this process causes progressive deterioration of motor coordination. Seeking to understand how post-translational modification of ATAXIN1 levels influences disease, we discovered that the RNA-binding protein PUMILIO1 (PUM1) not only directly regulates ATAXIN1 but also plays an unexpectedly important role in neuronal function. Loss of Pum1 caused progressive motor dysfunction and SCA1-like neurodegeneration with motor impairment, primarily by increasing Ataxin1 levels. Breeding Pum1+/- mice to SCA1 mice (Atxn1154Q/+) exacerbated disease progression, whereas breeding them to Atxn1+/- mice normalized Ataxin1 levels and largely rescued the Pum1+/- phenotype. Thus, both increased wild-type ATAXIN1 levels and PUM1 haploinsufficiency could contribute to human neurodegeneration. These results demonstrate the importance of studying post-transcriptional regulation of disease-driving proteins to reveal factors underlying neurodegenerative disease.
Bibliographical noteFunding Information:
We thank Dr. Haifan Lin (Yale Stem Cell Center and Department of Cell Biology, Yale University School of Medicine) for sharing the Pum1 mutant mice; A. McCall for helpful suggestions on analysis; X. Liu for genotyping; C. Spencer for behavioral training; C. Ljungberg for ISH analysis; D. Yu for confocal microscopy training; and members of the H.Y.Z. laboratory for helpful discussions. We also thank A. Ballabio, T. Klisch, S. Yamamoto, M. Rousseaux, M. Sardiello, C. Schaaf, C. Alcott, and V. Brandt for helpful suggestions and critical reading of the manuscript. This research was supported by R01NS027699-26 (to H.Y.Z.) and the RNA In Situ Hybridization, Confocal and Mouse Behavioral Cores at the BCM Intellectual and Developmental Disabilities Research Center (IDDRC; NIH/NICHHDP30-HD024064) and 1R01NS089664-01 (to R.V.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the National Institutes of Health.