Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels
- Authors
- Gennarino V.A.; Singh R.K.; White J.J.; De Maio A.; Han K.; Kim J.-Y.; Jafar-Nejad P.; Di Ronza A.; Kang H.; Sayegh L.S.; Cooper T.A.; Orr H.T.; Sillitoe R.V.; Zoghbi H.Y.
- Issue Date
- 2015
- Publisher
- Cell Press
- Citation
- Cell, v.160, no.6, pp 1087 - 1098
- Pages
- 12
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- Cell
- Volume
- 160
- Number
- 6
- Start Page
- 1087
- End Page
- 1098
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/8531
- DOI
- 10.1016/j.cell.2015.02.012
- ISSN
- 0092-8674
1097-4172
- 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 (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. © 2015 Elsevier Inc.
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- Appears in
Collections - 1. Basic Science > Department of Neuroscience > 1. Journal Articles
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