Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels.

Abstract

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 (Atxn1(154Q/+)) 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.

• Authors: Vincenzo A Gennarino, Ravi K Singh, Joshua J White, Antonia De Maio, Kihoon Han, Ji-Yoen Kim, Paymaan Jafar-Nejad, Alberto di Ronza, Hyojin Kang, Layal S Sayegh, Thomas A Cooper, Harry T Orr, Roy V Sillitoe, Huda Y Zoghbi
• Journal: Cell (Cell) Vol. 160 Issue 6 Pg. 1087-98 (Mar 12 2015) ISSN: 1097-4172 [Electronic] United States
• PMID: 25768905 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• 3' Untranslated Regions
• ATXN1 protein, human
• Antigens, Ly
• Ataxin-1
• Ataxins
• Atxn1 protein, mouse
• Ly6a protein, mouse
• Membrane Proteins
• MicroRNAs
• Nerve Tissue Proteins
• Nuclear Proteins
• RNA, Messenger
• RNA-Binding Proteins
• pumilio 1 protein, mouse

Topics

• 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, pathology)
• Nuclear Proteins (genetics)
• Nucleic Acid Conformation
• RNA Processing, Post-Transcriptional
• RNA Stability
• RNA, Messenger (chemistry)
• RNA-Binding Proteins (genetics)