Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels. Cell 2015 Mar 12;160(6):1087-98
Date
03/15/2015Pubmed ID
25768905Pubmed Central ID
PMC4383046DOI
10.1016/j.cell.2015.02.012Scopus ID
2-s2.0-84924559965 (requires institutional sign-in at Scopus site) 112 CitationsAbstract
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.
Author List
Gennarino VA, Singh RK, White JJ, De Maio A, Han K, Kim JY, Jafar-Nejad P, di Ronza A, Kang H, Sayegh LS, Cooper TA, Orr HT, Sillitoe RV, Zoghbi HYMESH terms used to index this publication - Major topics in bold
3' Untranslated RegionsAnimals
Antigens, Ly
Ataxin-1
Ataxins
Brain
Gene Knock-In Techniques
Haploinsufficiency
Humans
Membrane Proteins
Mice
Mice, Knockout
MicroRNAs
Mutation
Nerve Tissue Proteins
Neurodegenerative Diseases
Nuclear Proteins
Nucleic Acid Conformation
RNA Processing, Post-Transcriptional
RNA Stability
RNA, Messenger
RNA-Binding Proteins
