Ataxin-2 ASOs May Clear More Obstacles In ALS

Researchers are developing potential treatment strategies for ALS that target nuclear export in hopes to prevent key proteins including TDP-43 from building up in the cytoplasm of motor neurons (see April 2018 news). But according to a study led by the University of Michigan’s Sami Barmada, TDP-43 may exit the nucleus through multiple mechanisms suggesting that other approaches may be needed to reduce motor neuron toxicity in the disease (see April 2018 news; Archbold et al., 2018).

All clear. Treatment with Ataxin-2 ASOs restored the transport of proteins in and out of the nucleus of motor neurons, potentially reducing toxicity. [Courtesy of Zhang et al., 2018, Cell].

Now, a research team led by Johns Hopkins University’s Jeffrey Rothstein and Thomas Lloyd in Baltimore, Maryland report that increased stress in motor neurons may lead to a disruption in nucleocytoplasmic transport in ALS. And, reducing the buildup of key RNA granules that assemble during these tough times may help protect motor neurons in part, by clearing up these nuclear traffic jams.

The study found that during increased stress, key proteins needed to transport cargo between the nucleus and cytoplasm became sequestered into stress granules slowing nuclear traffic to a crawl – at least in iPS-derived C9orf72 ALS motor neurons (see figure). Blocking the assembly of these RNA granules by lowering levels of ataxin-2 restored nucleocytoplasmic transport, potentially reducing toxicity.

The results build on previous studies led by Aaron Gitler at Stanford University School of Medicine, which found that a single ataxin-2 antisense oligonucleotide treatment, delivered directly into the brain at the neonatal stage, improved motor function and increased the survival time of ALS model mice by more than 33% (see May 2017 news; Becker et al., 2017).

The study appeared on April 2 in Cell.

Together, the results suggest that reducing levels of ataxin-2 may help protect motor neurons in ALS by reducing the build-up of key proteins in the cytoplasm including TDP-43.

The findings come at the heels of a previous study led by Mayo Clinic’s Wilfried Rossoll in Jacksonville, Florida, which suggest that nuclear pores, the key gateway that mediates traffic in and out of the nucleus, become damaged in ALS through a TDP-43-based mechanism (see Jan 2018 news; Chou et al., 2018).

Efforts are underway to further evaluate ataxin-2 ASOs as a treatment for ALS, including sporadic disease (see May 2017 news). Stay tuned.


To learn more about ataxin-2 and the potential of ASOs as a potential therapy for ALS, check out Ataxin-2 ASOs Aim to De-stress ALS. To find out more about emerging therapies targeting nuclear export, check out Scientists Pore Over New Strategies To Tackle ALS.

Featured Paper

Zhang K, Daigle JG, Cunningham KM, Coyne AN, Ruan K, Grima JC, Bowen KE, Wadhwa H, Yang P, Rigo F, Taylor JP, Gitler AD, Rothstein JD, Lloyd TE. Stress Granule Assembly Disrupts Nucleocytoplasmic Transport. Cell. 2018 Apr 2. pii: S0092-8674(18)30305-2. [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].

Chou CC, Zhang Y, Umoh ME, Vaughan SW, Lorenzini I, Liu F, Sayegh M, Donlin-Asp PG, Chen YH, Duong DM, Seyfried NT, Powers MA, Kukar T, Hales CM, Gearing M, Cairns NJ, Boylan KB, Dickson DW, Rademakers R, Zhang YJ, Petrucelli L, Sattler R, Zarnescu DC, Glass JD, Rossoll W. TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci. 2018 Feb;21(2):228-239. [PubMed]

Archbold HC, Jackson KL, Arora A, Weskamp K, Tank EM, Li X, Miguez R, Dayton RD, Tamir S, Klein RL, Barmada SJ. TDP43 nuclear export and neurodegeneration in models of amyotrophic lateral sclerosis and frontotemporal dementia. Sci Rep. 2018 Mar 15;8(1):4606. [PubMed]

Further Reading

Scoles DR, Pulst SM. Oligonucleotide therapeutics in neurodegenerative diseases. RNA Biol. 2018 Mar 21:1-23. [PubMed].

Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):129-33. [PubMed]

Jovičić A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G, Kramer NJ, Gage FH, Van Den Bosch L, Robberecht W, Gitler AD. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci. 2015 Sep;18(9):1226-9. [PubMed]

Zhang K, Donnelly CJ, Haeusler AR, Grima JC, MAchamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61. [PubMed]








antisense oligonucleotides ASOs ataxin-2 disease-als nucleocytoplasmic transport sporadic ALS stress granules topic-preclinical
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