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Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models

Nature Genetics volume 44, pages 1302–1309 (2012)Cite this article

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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease primarily affecting motor neurons. Mutations in the gene encoding TDP-43 cause some forms of the disease, and cytoplasmic TDP-43 aggregates accumulate in degenerating neurons of most individuals with ALS. Thus, strategies aimed at targeting the toxicity of cytoplasmic TDP-43 aggregates may be effective. Here, we report results from two genome-wide loss-of-function TDP-43 toxicity suppressor screens in yeast. The strongest suppressor of TDP-43 toxicity was deletion of DBR1, which encodes an RNA lariat debranching enzyme. We show that, in the absence of Dbr1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP-43, preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of Dbr1 in a human neuronal cell line or in primary rat neurons is also sufficient to rescue TDP-43 toxicity. Our findings provide insight into TDP-43–mediated cytotoxicity and suggest that decreasing Dbr1 activity could be a potential therapeutic approach for ALS.

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Figure 1: DBR1 deletion suppresses TDP-43 toxicity in yeast.
Figure 2: DBR1 knockdown reduces TDP-43 toxicity in a human neuronal cell line.
Figure 3: Dbr1 knockdown reduces TDP-43 toxicity in primary rat neurons.
Figure 4: Dbr1 lariat debranching enzymatic activity is required for TDP-43 toxicity, and TDP-43 toxicity suppression is mediated by lariat intron accumulation.
Figure 5: Intronic lariats colocalize with TDP-43 cytoplasmic foci in yeast.

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Acknowledgements

We thank K. Lynch and S. Smith for helpful suggestions and discussions about RNA and splicing; T. Nakaya for advice and assistance with lentivirus transduction experiments and analysis; C. Kurischko for advice and assistance with visualizing P bodies and stress granules; Q. Mitrovich and A. Plocik for advice with running the two-dimensional nucleic acid gels; S. Collins and D. Cameron for useful advice and assistance in performing the data analysis for screen 2; B. Hodges, D. Hosangadi, P. Patel, P. Nathanson and C. Mrejen for assistance with yeast experiments; J. Epstein and A. Raphael for critical comments on the manuscript and helpful suggestions; and G. Howard for editorial assistance. A. Elden helped with initial stages of this project. We are grateful to J. Gerst (Weizmann Institute) for providing the yeast m-TAG plasmids, R. Parker (University of Arizona) for sharing the P-body and stress granule marker plasmids and J. Weibezahn (University of California, San Francisco) for providing temperature-sensitive CDC48 (cdc48-3, SM 4783) and wild-type CDC48 isogenic (SM 5124) yeast strains. We thank B. Schwer (Weill Cornell Medical College) for providing the yeast mutant Dbr1 expression plasmids. We thank C. Boone (University of Toronto) for the MATα strain Y7092. This work was supported by US National Institutes of Health (NIH) Director's New Innovator Awards 1DP2OD004417 (to A.D.G.) and 1DP2OD002177 (to J.S.), NIH grants NS065317 and NS065317 (to A.D.G.), NS067354 (to J.S.), GM084448, GM084279, GM081879 and GM098101 (to N.J.K.), NS39074 and NS045491 (to S.F.) and NS072233 (to S.J.B.), a New Scholar in Aging Award from the Ellison Medical Foundation (to J.S.), a grant from the Packard Center for ALS Research at Johns Hopkins (A.D.G. and J.S.), a grant from the Consortium for Frontotemporal Research (to R.V.F.), NIH grant 2P01AG02074 (to S.F.), a grant from the ALS Association (to S.F.) and the Taube-Koret Center and Hellman Family Foundation (to S.F.). A.D.G. is a Pew Scholar in the Biomedical Sciences, supported by The Pew Charitable Trusts, and a Rita Allen Foundation Scholar. N.J.K. is a Searle Scholar and a Keck Young Investigator. R.V.F. is an Investigator of the Gladstone Institutes. The J. David Gladstone Institutes received support from National Center for Research Resources Grant RR18928.

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Author notes

  1. Maria Armakola and Matthew J Higgins: These authors contributed equally to this work.

  2. Robert V Farese and Aaron D Gitler: These authors jointly directed this work.

Authors and Affiliations

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

    Maria Armakola, Matthew D Figley, Xiaodong Fang & Aaron D Gitler

  2. Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Maria Armakola

  3. Gladstone Institute of Cardiovascular Disease, J David Gladstone Institutes, San Francisco, California, USA

    Matthew J Higgins, Nevan J Krogan & Robert V Farese Jr

  4. Gladstone Institute of Neurological Disease, Taube-Koret Center, Hellman Family Foundation Program, J David Gladstone Institutes, San Francisco, California, USA

    Sami J Barmada & Steven Finkbeiner

  5. Department of Neurology, University of California, San Francisco, San Francisco, California, USA.,

    Sami J Barmada & Steven Finkbeiner

  6. Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Emily A Scarborough, Zamia Diaz & James Shorter

  7. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.,

    Nevan J Krogan

  8. California Institute for Quantitative Biosciences, San Francisco, California, USA

    Nevan J Krogan

  9. Department of Physiology, University of California, San Francisco, San Francisco, California, USA.,

    Steven Finkbeiner

  10. Department of Medicine, University of California, San Francisco, San Francisco, California, USA.,

    Robert V Farese Jr

  11. Department of Biochemistry & Biophysics, University of California, San Francisco, San Francisco, California, USA.,

    Robert V Farese Jr

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Contributions

M.A., M.J.H., M.D.F., S.J.B., J.S., N.J.K., S.F., R.V.F. and A.D.G. designed the experiments. M.A., M.J.H., M.D.F., S.J.B., J.S., E.A.S., Z.D., X.F. and A.D.G. performed the research. M.A., M.J.H., M.D.F., S.J.B., J.S., N.J.K., S.F., R.V.F. and A.D.G. analyzed and interpreted data. M.A., M.J.H., M.D.F., S.J.B., S.F., R.V.F. and A.D.G. wrote the manuscript with contributions from all authors.

Corresponding authors

Correspondence to Robert V Farese Jr or Aaron D Gitler.

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A.D.G. is an inventor on patents and patent applications that have been licensed to FoldRx.

Supplementary information

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Supplementary Figures 1–6, Supplementary Table 1 and Supplementary Note (PDF 7108 kb)

Supplementary Data

Results of TDP-43 toxicity modifier screen (supplied as separate Excel file) (XLSX 542 kb)

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Armakola, M., Higgins, M., Figley, M. et al. Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nat Genet 44, 1302–1309 (2012). https://doi.org/10.1038/ng.2434

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