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RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats

Abstract

Nucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. Unconventional translation (RAN translation) of C9orf72 repeats generates dipeptide repeat proteins that can cause neurodegeneration. We performed a genetic screen for regulators of RAN translation and identified small ribosomal protein subunit 25 (RPS25), presenting a potential therapeutic target for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia and other neurodegenerative diseases caused by nucleotide repeat expansions.

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Fig. 1: RPS25 is required for efficient RAN translation in yeast and human cells.
Fig. 2: RPS25 knockdown reduces poly(GP) levels in C9orf72 ALS patient iPSCs.
Fig. 3: RPS25 knockdown reduces RAN translation products and extends lifespan in a Drosophila C9orf72 model and in ALS patient-derived iMNs.

Data availability

The data that support the findings of the present study are available from the corresponding author upon request.

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Acknowledgements

This work was supported by National Institutes of Health (NIH) grants nos. R35NS097263 (A.D.G.), AI099506 (J.D.P), AG064690 (A.D.G. and J.D.P.), R35NS097273 (L.P.), P01NS099114 (T.F.G., L.P) and R01NS097850 (J.K.I.), the Robert Packard Center for ALS Research at Johns Hopkins (L.P., A.D.G.), Target ALS (L.P., A.D.G., T.F.G.), the US Department of Defense (J.D.P., A.D.G., J.K.I.), the Muscular Dystrophy Association (J.K.I.), 2T32HG000044-21 NIHGRI training grant (S.B.Y.), the Brain Rejuvenation Project of the Wu Tsai Neurosciences Institute (A.D.G.), the European Research Council grant no. ERC-2014-CoG-648716 (A.M.I.), Alzheimer’s Research UK (A.M.I.) and the Medical Research Council (A.M.I.). J.K.I. is supported by funding for a New York Stem Cell Foundation-Robertson Investigatorship. We thank Dr. L. Ranum (University of Florida) for sharing the huntingtin poly(alanine) antibody. We thank M. Bassik for the HeLa Cas9–BFP cell lines. We thank H. Tricoire (French National Center for Scientific Research) for the generous gift of the original elavGS 301.2 line.

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Contributions

This work was performed and the paper written by S.B.Y. under the mentorship of A.D.G. T.F.G. contributed ELISA assays to detect RAN peptides and analyses under the mentorship of L.P. T.N., I.G. and A.T. contributed Drosophila studies under the mentorship of L.P. and A.M.I. N.R.G. contributed to polysome profiling studies and analyses, under the mentorship of M.B. R.G. contributed to RAN translation studies and analyses, under the mentorship of J.D.P. Y.S. and G.R. contributed induced motor neuron studies and analyses, under the mentorship of J.K.I. N.J.K. contributed to studies of ATXN2 RAN translation. L.N., S.F. and T.J.I.D. contributed to studies of C9orf72 RAN translation.

Corresponding author

Correspondence to Aaron D. Gitler.

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Competing interests

A.D.G. has served as a consultant for Aquinnah Pharmaceuticals, Prevail Therapeutics and Third Rock Ventures and is a scientific founder of Maze Therapeutics.

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Peer review information: Nature Neuroscience thanks D. Dormann and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Yamada, S.B., Gendron, T.F., Niccoli, T. et al. RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats. Nat Neurosci 22, 1383–1388 (2019). https://doi.org/10.1038/s41593-019-0455-7

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