A Stress Reliever for Neurons in ALS? Scientists Say It’s a Possibility.

The accumulation of RNA stress granules in the cytoplasm may be a key source of motor neuron toxicity in ALS. But how to reduce this buildup remains unclear.

A stress reliever? Lowering levels of Staufen levels 50% nearly eliminated stress granule-like structures decorated by ataxin-2 (see arrows) in key neurons in the brain – at least in a mouse model of spinocerebellar ataxia (SCA2).[Courtesy of Paul et al., 2018, Nature Communications.]

Now, a research team led by University of Utah’s Stefan Pulst reports that increased levels of the stress granule-associated protein Staufen1 can be detected in skin cells from at least one case of TDP43-linked ALS.

What’s more, Staufen 1 co-localizes with ataxin-2 on stress granule-like structures that build up in the brain – at least in the neurodegenerative brain disorder spinocerebrellar ataxia 2 (SCA2) according to a post-mortem tissue analysis. And, lowering levels of Staufen1 by 50% nearly eliminates these structures in SCA2 model mice via an autophagy-based mechanism (see figure, arrows).

Together, the findings open up the possibility that reducing levels of Staufen1 may help protect neurons against neurodegenerative diseases including ALS by helping to clear stress granules out of the cytoplasm. The approach builds in part on previous studies, led by Aaron Gitler at Stanford University School of Medicine in California, which found that ataxin-2 promotes the recruitment of TDP-43 to stress granules, facilitating its aggregation and potentially its toxicity in the disease (see May 2017 news; Elden et al., 2010; Kim et al., 2014; Becker et al., 2017). Efforts to develop an antisense oligonucleotide therapy targeting Staufen1 are currently underway.

The findings appeared on September 7 in Nature Communications.

Meanwhile, Gitler’s team is setting its sights on ataxin-2 in ALS. The antisense oligonucleotide-based strategy is being developed in partnership with Ionis Pharmaceuticals in Carlsbad, California (see May 2017 news). The approach, according to studies led by Johns Hopkins University School of Medicine’s Jeff Rothstein in Baltimore, Maryland, may also reduce neurotoxicity in ALS by helping clear up nuclear traffic jams (see May 2018 news). The strategy is also being developed by Pulst’s team as a potential treatment for SCA2. Stay tuned.


To find out more about the emerging role of Staufen1 in neurodegeneration, check out RNA-binding Protein Linked To Ataxin-2 Toxicity. To learn more about the role of stress granules and the challenges to tackle them, check out A New Treatment Approach May Perk Up the ALS Pipeline.


Paul S, Dansithong W, Figueroa KP, Scoles DR, Pulst SM. Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration. Nat Commun. 2018 Sep 7;9(1):3648. [PubMed].

Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, Messing J, Kim HJ, Soriano A, Auburger G, Pulst SM, Taylor JP, Rigo F, Gitler AD. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature. 2017 Apr 20;544(7650):367-371. [PubMed].

Kim HJ, Raphael AR, LaDow ES, McGurk L, Weber RA, Trojanowski JQ, Lee VM, Finkbeiner S, Gitler AD, Bonini NM. Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet. 2014 Feb;46(2):152-60. [PubMed].

Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, Padmanabhan A, Clay-Falcone D, McCluskey L, Elman L, Juhr D, Gruber PJ, Rüb U, Auburger G, Trojanowski JQ, Lee VM, Van Deerlin VM, Bonini NM, Gitler AD. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010 Aug 26;466(7310):1069-75. [PubMed].

Further Reading

Li YR, King OD, Shorter J, Gitler AD. Stress granules as crucibles of ALS pathogenesis. J Cell Biol. 2013 Apr 29;201(3):361-72. [PubMed].

Scoles DR, Meera P, Schneider MD, Paul S, Dansithong W, Figueroa KP, Hung G, Rigo F, Bennett CF, Otis TS, Pulst SM. Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature. 2017 Apr 20;544(7650):362-366. [PubMed].

antisense oligonucleotides ASOs ataxin-2 disease-als disease-sca2 RNA granules staufen1 stress granules
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