Article | Published:

REST and stress resistance in ageing and Alzheimer’s disease

Nature volume 507, pages 448454 (27 March 2014) | Download Citation

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  • An Addendum to this article was published on 16 November 2016

Abstract

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer’s disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer’s disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer’s disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

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Gene Expression Omnibus

Data deposits

Data are available in the Gene Expression Omnibus (GEO) under accession GSE53890.

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Acknowledgements

We thank members of the Yankner laboratory for suggestions and discussion, Monlan Yuan, Allison Harwick, Kelly Dakin and Gregory Klein for assistance, and Cheng Li and Dana Gabuzda for helpful discussion. We also acknowledge the Rush Alzheimer's Disease Center, the Brigham and Women’s Hospital Brain Bank, the Massachusetts General Hospital ADRC Brain Bank, and the Kathleen Price Bryan Brain Bank at Duke University for providing tissue samples. This work was supported by an NIH Director’s Pioneer Award (DP1OD006849) and NIH grants PO1AG27916 and RO1AG26651 to B.A.Y., RO1GM072551 to M.P.C., P30AG10161, R01AG15819 and R01AG17917 to D.A.B., and a grant from the Glenn Foundation for Medical Research to B.A.Y. J.Z. is a Molecular Biology of Neurodegeneration fellow at Harvard Medical School.

Author information

Affiliations

  1. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Tao Lu
    • , Liviu Aron
    • , Joseph Zullo
    • , Ying Pan
    • , Haeyoung Kim
    • , Tun-Hsiang Yang
    • , Hyun-Min Kim
    • , Derek Drake
    • , Monica P. Colaiácovo
    •  & Bruce A. Yankner
  2. Department of Biostatistics and Computational Biology, Dana-Faber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA

    • Yiwen Chen
    •  & X. Shirley Liu
  3. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois 60612, USA

    • David A. Bennett

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Contributions

T.L., L.A., J.Z., Y.P., H.K., and H.-M.K. performed experiments. T.L., L.A., J.Z., M.C. and B.A.Y. contributed to the overall study design. T.L., Y.C., T.-H.Y., D.D. and X.L. performed informatics analysis. D.A.B. contributed tissue samples, cognitive test data and analysis. B.A.Y. directed the study and B.A.Y., T.L., L.A. and J.Z. wrote the manuscript, which was edited by all the coauthors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bruce A. Yankner.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    Human Brain Specimens. This table provides demographic, diagnostic, physical and source data for human brain specimens used in the study.

  2. 2.

    Supplementary Table 2

    Primers for PCR and ChIP. This table provides sequence, amplicon and accession number data on PCR primers used in the study.

  3. 3.

    Supplementary Table 3

    This table lists Antibodies and Reagents. This file was replaced on 16 November 2016 - see http://www.nature.com/doifinder/10.1038/nature20579 for details.

  4. 4.

    Supplementary Table 4a

    ChIP-seq Data: SH-SY5Y Cells. This table provides data on locations of binding sites, binding fold changes relative to input controls, statistical significance and RE1 motif analysis.

  5. 5.

    Supplementary Table 4b

    ChIP-seq Data: SH-SY5Y Cells/Lithium Chloride. This table provides the same categories of information as Table 4a but for SH-SY5Y cells that were treated with lithium chloride.

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DOI

https://doi.org/10.1038/nature13163

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