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 journalArticle

47 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1087-1098
Number of pages12
JournalCell
Volume160
Issue number6
DOIs
StatePublished - Mar 15 2015

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Spinocerebellar Ataxias
Haploinsufficiency
Neurodegenerative diseases
Breeding
RNA-Binding Proteins
Mutant Proteins
Neurons
Toxicity
Deterioration
Ataxia
Post Translational Protein Processing
Neurodegenerative Diseases
Disease Progression
Phenotype
Proteins

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Gennarino, V. A., Singh, R. K., White, J. J., De Maio, A., Han, K., Kim, J. Y., ... Zoghbi, H. Y. (2015). Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels. Cell, 160(6), 1087-1098. https://doi.org/10.1016/j.cell.2015.02.012

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

In: Cell, Vol. 160, No. 6, 15.03.2015, p. 1087-1098.

Research output: Contribution to journalArticle

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, HY 2015, 'Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels', Cell, vol. 160, no. 6, pp. 1087-1098. https://doi.org/10.1016/j.cell.2015.02.012
Gennarino VA, Singh RK, White JJ, De Maio A, Han K, Kim JY et al. Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels. Cell. 2015 Mar 15;160(6):1087-1098. https://doi.org/10.1016/j.cell.2015.02.012
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. / Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels. In: Cell. 2015 ; Vol. 160, No. 6. pp. 1087-1098.
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