Pumilio1 Haploinsufficiency Leads to SCA1-like Neurodegeneration by Increasing Wild-Type Ataxin1 Levels

• Published in: Cell Vol. 160; no. 6; pp. 1087 - 1098
• Main Authors: Gennarino, Vincenzo A., Singh, Ravi K., White, Joshua J., De Maio, Antonia, Han, Kihoon, Kim, Ji-Yoen, Jafar-Nejad, Paymaan, di Ronza, Alberto, Kang, Hyojin, Sayegh, Layal S., Cooper, Thomas A., Orr, Harry T., Sillitoe, Roy V., Zoghbi, Huda Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.03.2015
• Subjects: 3' Untranslated Regions; Animals; Antigens, Ly - genetics; Ataxin-1; Ataxins; Brain - metabolism; Gene Knock-In Techniques; Haploinsufficiency; Humans; Membrane Proteins - genetics; Mice; Mice, Knockout; MicroRNAs - metabolism; Mutation; Nerve Tissue Proteins - genetics; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - pathology; Nuclear Proteins - genetics; Nucleic Acid Conformation; RNA Processing, Post-Transcriptional; RNA Stability; RNA, Messenger - chemistry; RNA-Binding Proteins - genetics
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.02.012

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. [Display omitted] •The RNA-binding protein PUMILIO1 regulates levels of ATAXIN1 protein and mRNA•A modest increase in wild-type Ataxin1 levels is enough to cause neurodegeneration•Pumilio1 haploinsufficiency accelerates SCA1 disease progression•Ataxin1 haploinsufficiency rescues Pumilio1+/− phenotypes Pumilio1 is an RNA-binding protein that binds Ataxin1 mRNA and regulates its stability. Haploinsufficiency of Pumilio1 results in an increase in Ataxin1 levels, leading to progressive motor dysfunction and degeneration of Purkinje cells, features typical of spinocerebellar ataxia type 1. These data suggest that either haploinsufficiency of PUMILIO1 or duplication of ATAXIN1 could contribute to neurodegeneration in humans.