An RNA-binding protein never before linked to neurodegeneration may conspire with ataxin-2 to decimate the neuronal transcriptome. According to a September 7 paper in Nature Communications, the cytoplasmic Staufen1 accrues in neurons when mutant ataxin-2, which also binds RNA, suppresses autophagy. Staufen-1 then initiates degradation of certain mRNAs, report scientists led by Stefan Pulst, University of Utah Health, Salt Lake City. Several of these mRNAs are important for the health of cerebellar Purkinje cells, which die in spinocerebellar ataxia type 2 (SCA2). “It suggests that reducing overabundant Staufen1 would have a therapeutic effect,” Pulst told Alzforum. The findings have implications beyond SCA2, since ataxin-2 variants are risk factors for amyotrophic lateral sclerosis and other diseases. Pulst reports that Staufen1 also accumulates in cultured fibroblasts from ALS patients with mutations in the TDP-43 gene.

  • Mutant ATXN2 slows autophagy, stranding Staufen1 in cytoplasm.
  • Excess Staufen1 binds and degrades mRNAs needed in Purkinje cells.
  • Lowering Staufen1 may be a therapeutic option in SCA2.

Repeat CAG trinucleotides in exon-1 of the ataxin-2 gene encode a polyglutamine expansion that makes the protein prone to aggregate. Normally, ataxin-2 contributes to the formation of stress granules, which sequester and silence mRNAs to help cells cope in times of stress. Previously, scientists found Staufen-1 in stress granules of mammalian cells, as well (Thomas et al., 2009). This protein binds in the 3' untranslated region of mRNAs that assume certain double-stranded secondary structures, then it recruits the RNA helicase Upf1, which initiates their degradation (Park and Maquat, 2013). This system modulates the half-lives of specific mRNAs in the cytoplasm.

First author Sharan Paul and colleagues wanted to see if these two components of stress granules—ataxin-2 and Staufen1—co-localized in neurodegenerative disease. In fibroblasts from SCA2 patients, and from ALS patients carrying a G298S mutation in TDP-43, which has been linked to the disease (Van Deerlin et al., 2008), immunofluorescence revealed both proteins together in stress granules. The same was true in Purkinje cells of ATXN2Q127 mice, which express full-length human ataxin with a 127-amino-acid polyglutamine repeat (Hansen et al., 2013). Interestingly, Staufen1 accumulated not only in the cerebella from the ATXN2Q127 mice, but in the fibroblasts from the SCA2 patients and ALS patients. These associations suggest high Staufen1 levels could be characteristic of multiple neurodegenerative diseases.

Same time, same place. In 24-week-old mice, mutant ataxin-2 (green) aggregates (white arrows) with Staufen1 (red) in cerebellar Purkinje cells. [Courtesy of Paul et al., 2018. Nat Comm.]

To find out why Staufen1 levels rose, the authors examined protein degradation mechanisms in HEK293 cells that carry one mutant ATXN2 allele. They found that as autophagy slowed down, Staufen1 climbed. The results hint that mutant ATXN2 impairs autophagy, causing Staufen1 to build up in the cytoplasm.

What effect might excess Staufen1 have on the cell? In HEK293 cells, mRNAs for PCP2 and CALB1 fell by 30 to 40 percent compared with controls. Both are highly expressed in Purkinje cells and play important roles in their health, potentially explaining why these neurons die in SCA2 mouse models (Hansen et al., 2013). According to immunoprecipitation, Staufen1 directly bound the 3' UTR of PCP2 mRNA. The findings hint that too much Staufen1 leads to a dearth of PCP2, and possibly other proteins needed for survival of Purkinje cells, the authors wrote. They did not report whether Staufen also binds CALB1.

Would lowering Staufen1 restore mRNA levels? In SCA2 cells, a small interfering RNA against the Staufen-1 transcript normalized PCP2 levels. In genetic crosses, ATXN2Q127 mice deficient in one copy of Staufen1 expressed more PCP2, CALB1, RGS8, PCP4, Fam107b, and Homer3 than did ATXN2Q127 controls. All these genes are normally highly expressed in Purkinje cells but reduced in ATXN2Q127 mice. Crosses were also able to balance longer on an accelerating rotarod than ATXN2Q127 mice, though they didn’t hang on as long as wild-type controls.

Together, these findings paint Staufen1 as a novel target for treatment of SCA2 and possibly other neurodegenereative diseases, said Pulst. He plans to test other disease models for elevated Staufen1, and find what other kinds of cellular stressors upregulate the protein.

“This paper tells us a lot about the biology of spinocerebellar ataxia 2,” said Sheng-Han Kuo, Columbia University, New York. “Maybe this will lead to an interesting new therapeutic approach,” he said. He added that it would be interesting to see which other RNAs are downregulated by excess Staufen1, and which are normalized after it is reined in.

Lindsay Becker, a graduate student in Aaron Gitler’s lab at Stanford University, California, agreed that the paper was interesting, particularly the direct link between AXTN2 expression and the transcriptomic changes the Pulst lab previously described in ATXN2 mice.

Becker and Pulst have separately developed anti-sense oligonucleotides against ATXN2 that have proven effective in reducing motor impairments in mouse models of SCA2 and ALS (Apr 2017 news). It may be that ATXN2 makes a better target than Staufen1 because it hits more pathogenic pathways, said Harry Orr, University of Minnesota, Minneapolis. “There are multiple pathogenic pathways in all these different neurodegenerative diseases, and the further one goes down the pathogenic cascade, the smaller the contribution any one pathway has on the overall phenotype,” he said. “I’m a big proponent of focusing on the top of the whole cascade.” Pulst said it would take more work to determine the better target. Kuo thinks both might fit into a multitarget approach.—Gwyneth Dickey Zakaib


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News Citations

  1. Two For One? ASOs for Ataxin Allay ALS and SCA2 in Mice

Paper Citations

  1. . Mammalian Staufen 1 is recruited to stress granules and impairs their assembly. J Cell Sci. 2009 Feb 15;122(Pt 4):563-73. PubMed.
  2. . Staufen-mediated mRNA decay. Wiley Interdiscip Rev RNA. 2013 Jul-Aug;4(4):423-35. Epub 2013 May 16 PubMed.
  3. . TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008 May;7(5):409-16. Epub 2008 Apr 7 PubMed.
  4. . Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2. Hum Mol Genet. 2013 Jan 15;22(2):271-83. Epub 2012 Oct 18 PubMed.

Further Reading


  1. . Spinocerebellar Ataxia Type 2. Adv Exp Med Biol. 2018;1049:175-195. PubMed.

Primary Papers

  1. . Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration. Nat Commun. 2018 Sep 7;9(1):3648. PubMed.