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Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS

Nature Neuroscience volume 18, pages 12261229 (2015) | Download Citation

Abstract

C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansions cause neurodegeneration in cell culture and in animal models. We performed two unbiased screens in Saccharomyces cerevisiae and identified potent modifiers of DPR toxicity, including karyopherins and effectors of Ran-mediated nucleocytoplasmic transport, providing insight into potential disease mechanisms and therapeutic targets.

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Acknowledgements

We thank J. Ravits and C. Lagier-Tourenne (University of California, San Diego) for sharing the control and C9orf72 ALS patient fibroblasts used in this study. We acknowledge microscopy assistance from the Stanford Neuroscience Microscopy Service, supported by US National Institutes of Health (NIH) grant NS069375. This work was supported by NIH grants 1R01NS065317 and 1R01NS073660 (A.D.G.). A.D.G. is supported by the Packard Center for ALS Research at Johns Hopkins and Target ALS. A.J. is supported by the Dean's Postdoctoral Fellowship from Stanford University. S.S. is a recipient of NIH K99/R00 Award (NS091538) and Target ALS Springboard Fellowship. J.M. and F.H.G. are supported by JPB Foundation, the Helmsley Foundation and the Mathers Foundation. Additional research funding was provided by the KU Leuven, the European Research Council in the context of the European's Seventh Framework Programme (FP7/2007-2013 and ERC grant agreement 340429), the Fund for Scientific Research Flanders (FWO-Vlaanderen) G.0983.14N, the Interuniversity Attraction Poles Programme P7/16 initiated by the Belgian Science Policy Office, the Association Belge contre les Maladies Neuro-Musculaires (ABMM), the ALS Liga (Belgium) and the Opening the Future fund. S.B. received a fellowship from the Agency for Innovation by Science and Technology IWT. E.B. holds a postdoctoral fellowship from FWO-Vlaanderen. W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders.

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Affiliations

  1. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

    • Ana Jovičić
    • , Noori Chai
    • , Shizuka B Yamada
    • , Joseph W Paul III
    • , Gregor Bieri
    • , Nicholas J Kramer
    •  & Aaron D Gitler
  2. Salk Institute for Biological Studies, Sanford Consortium for Regenerative Medicine, La Jolla, California, USA.

    • Jerome Mertens
    • , Joseph R Herdy
    •  & Fred H Gage
  3. KU Leuven–University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium.

    • Steven Boeynaems
    • , Elke Bogaert
    • , Ludo Van Den Bosch
    •  & Wim Robberecht
  4. Vlaams Instituut voor Biotechnologie (VIB), Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium.

    • Steven Boeynaems
    • , Elke Bogaert
    • , Ludo Van Den Bosch
    •  & Wim Robberecht
  5. Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, California, USA.

    • Noori Chai
    • , Gregor Bieri
    •  & Nicholas J Kramer
  6. Department of Biology, Stanford University, Stanford, California, USA.

    • Shizuka B Yamada
  7. Ludwig Institute for Cancer Research, Departments of Cellular and Molecular Medicine and of Neurosciences, University of California at San Diego, La Jolla, California, USA.

    • Shuying Sun
  8. University Hospitals Leuven, Department of Neurology, Leuven, Belgium.

    • Wim Robberecht

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Contributions

A.J. designed and performed the yeast experiments with help from N.C., S.B.Y., J.W.P., G.B. and N.J.K. S.B. and E.B. generated and characterized some yeast expression plasmids with direction from L.V.D.B. and W.R. A.J. performed the mouse primary neuron experiments. A.J., S.S., J.M. and J.R.H. worked together on the human iN experiments with direction from F.H.G. A.J. and A.D.G. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Aaron D Gitler.

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DOI

https://doi.org/10.1038/nn.4085

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