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

Cell. 2015 Mar 12;160(6):1087-98. doi: 10.1016/j.cell.2015.02.012.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Neurodegenerative Diseases / pathology
  • Nuclear Proteins / genetics*
  • Nucleic Acid Conformation
  • RNA Processing, Post-Transcriptional
  • RNA Stability
  • RNA, Messenger / chemistry
  • RNA-Binding Proteins / genetics*


  • 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