An incomplete grasp of how the G4C2 repeat expansion in C9orf72 leads to amyotrophic lateral sclerosis and frontotemporal dementia has hindered progress in treatment development. Now, a study has combined unbiased genetic screens and CRISPR–Cas9 gene editing to validate known molecular pathways and identify novel therapeutic targets involved in G4C2 repeat pathogenesis.
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References
Boeynaems, S. et al. Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Sci. Rep. 6, 20877 (2016).
Freibaum, B. D. et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525, 129–133 (2015).
Jovicic, A. et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat. Neurosci. 18, 1226–1229 (2015).
Zhang, K. et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56–61 (2015).
Kramer, N. J. et al. CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity. Nat. Genet. (2018).
Zhang, Y. J. et al. Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol. 128, 505–524 (2014).
Schludi, M. H. et al. Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol. 130, 537–555 (2015).
Zhang, Y. J. et al. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat. Neurosci. 19, 668–677 (2016).
Shi, Y. et al. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat. Med. 24, 313–325 (2018).
Batra, R. et al. Elimination of toxic microsatellite repeat expansion RNA by RNA-targeting Cas9. Cell 170, 899–912.e10 (2017).
Acknowledgements
This work was supported by the Canadian Institute of Health Research (S.P.); National Institutes of Health/National Institute of Neurological Disorders and Stroke (R35NS097273 (L.P.); P01NS084974 (L.P.); P01NS099114 (L.P.); R01NS088689 (L.P.); R35NS097263 (L.P.); R21NS084528 (L.P.)); National Institute of Environmental Health Services (R01ES20395 (L.P.)); Department of Defense (ALSRP AL130125 (L.P.)); Mayo Clinic Foundation (L.P.); Amyotrophic Lateral Sclerosis Association (L.P.), Robert Packard Center for ALS Research at Johns Hopkins (L.P.), and Target ALS (L.P.). We would like to thank C. Cook, T. Gendron and Y.-J. Zhang for their thoughtful critiques.
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Pickles, S., Petrucelli, L. CRISPR expands insight into the mechanisms of ALS and FTD. Nat Rev Neurol 14, 321–323 (2018). https://doi.org/10.1038/s41582-018-0005-z
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DOI: https://doi.org/10.1038/s41582-018-0005-z
