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

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

Research output: Contribution to journalArticlepeer-review

112 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1087-1098
Number of pages12
Issue number6
StatePublished - Mar 15 2015

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© 2015 Elsevier Inc.


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