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‘Forward genetics’ and the causes of ALS

Nature Reviews Molecular Cell Biology volume 20, page 67 (2019)Cite this article

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For over 20 years I have witnessed antagonisms between proponents of hypothesis-driven research and supporters of unbiased screens (so-called big-data experiments), the latter of which are often dismissed as ‘fishing expeditions’ unworthy of true scientists (and guaranteed to sink grant proposals). Gitler and colleagues combined unbiased genetic screens with intuition testing across three species (yeast, flies and humans) to study the causes underlying the fatal human neurological disease amyotrophic lateral sclerosis (ALS). Vindicating the screening approach, their results are of a beauty and completeness rarely seen in contemporary research.

Affected neurons of virtually all ALS patients display pathological accumulation, in cytoplasmic inclusions, of the DNA-binding protein TDP43. Capitalizing on concepts developed by Susan Lindquist, Gitler suggested that yeast cells could be coerced to model ALS, and his team went on to perform an unbiased genetic screen to identify suppressors or enhancers of TDP43 toxicity. By expressing 5,500 individual yeast genes in a yeast strain expressing human DP43, they identified PBP1 as an enhancer of TDP43 toxicity. PBP1 is the orthologue of human ATXN2 (which encodes ataxin-2), which causes neurodegeneration when carrying very long polyglutamine tract expansions.

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References

Original articles

  • Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010)

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  • Becker, C. K. et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544, 367–371 (2017)

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  1. Institute of Neuropathology, University of Zurich,, CH-8002, Zurich, Switzerland

    Adriano Aguzzi

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  1. Adriano Aguzzi
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Correspondence to Adriano Aguzzi.

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Aguzzi, A. ‘Forward genetics’ and the causes of ALS. Nat Rev Mol Cell Biol 20, 67 (2019). https://doi.org/10.1038/s41580-018-0062-6

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