Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration

Nature volume 452, pages 887–891 (2008)Cite this article

Abstract

Neurodegeneration can be triggered by genetic or environmental factors. Although the precise cause is often unknown, many neurodegenerative diseases share common features such as protein aggregation and age dependence. Recent studies in Drosophila have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) against activity-induced neurodegeneration and injury-induced axonal degeneration1,2. Here we show that NMNAT overexpression can also protect against spinocerebellar ataxia 1 (SCA1)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heat-shock protein 70 (Hsp70). NMNAT displays chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of poly-glutamine expanded protein and recruited with the chaperone Hsp70 into protein aggregates. Our results implicate NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection. Our studies provide an entry point for understanding how normal neurons maintain activity, and offer clues for the common mechanisms underlying different neurodegenerative conditions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: NMNAT suppresses toxicity induced by ataxin-1.
Figure 2: NMNAT acts as a chaperone in cultured cells.
Figure 3: Endogenous and overexpressed NMNAT proteins are recruited with Hsp70 into the hAtx-1[82Q] aggregates.
Figure 4: In vivo and in vitro chaperone activity assays.

Similar content being viewed by others

References

  1. Zhai, R. G. et al. Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity. PLoS Biol. 4, e416 (2006)

    Article  Google Scholar 

  2. MacDonald, J. M. et al. The Drosophila cell corpse engulfment receptor draper mediates glial clearance of severed axons. Neuron 50, 869–881 (2006)

    Article  CAS  Google Scholar 

  3. Gillingwater, T. H. & Ribchester, R. R. Compartmental neurodegeneration and synaptic plasticity in the WldS mutant mouse. J. Physiol. (Lond.) 534, 627–639 (2001)

    Article  CAS  Google Scholar 

  4. Mack, T. G. et al. Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nature Neurosci. 4, 1199–1206 (2001)

    Article  CAS  Google Scholar 

  5. Ribchester, R. R. et al. Persistence of neuromuscular junctions after axotomy in mice with slow Wallerian degeneration (C57BL/WldS). Eur. J. Neurosci. 7, 1641–1650 (1995)

    Article  CAS  Google Scholar 

  6. Hoopfer, E. D. et al. Wlds protection distinguishes axon degeneration following injury from naturally occurring developmental pruning. Neuron 50, 883–895 (2006)

    Article  CAS  Google Scholar 

  7. Ludwin, S. K. & Bisby, M. A. Delayed wallerian degeneration in the central nervous system of Ola mice: an ultrastructural study. J. Neurol. Sci. 109, 140–147 (1992)

    Article  CAS  Google Scholar 

  8. Gillingwater, T. H., Haley, J. E., Ribchester, R. R. & Horsburgh, K. Neuroprotection after transient global cerebral ischemia in WldS mutant mice. J. Cereb. Blood Flow Metab. 24, 62–66 (2004)

    Article  CAS  Google Scholar 

  9. Ferri, A., Sanes, J. R., Coleman, M. P., Cunningham, J. M. & Kato, A. C. Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease. Curr. Biol. 13, 669–673 (2003)

    Article  CAS  Google Scholar 

  10. Samsam, M. et al. The WldS mutation delays robust loss of motor and sensory axons in a genetic model for myelin-related axonopathy. J. Neurosci. 23, 2833–2839 (2003)

    Article  CAS  Google Scholar 

  11. Sajadi, A., Schneider, B. L. & Aebischer, P. WldS-mediated protection of dopaminergic fibers in an animal model of Parkinson disease. Curr. Biol. 14, 326–330 (2004)

    Article  CAS  Google Scholar 

  12. Conforti, L. et al. A Ufd2/D4Cole1e chimeric protein and overexpression of Rbp7 in the slow Wallerian degeneration (WldS) mouse. Proc. Natl Acad. Sci. USA 97, 11377–11382 (2000)

    Article  CAS  ADS  Google Scholar 

  13. Conforti, L. et al. NAD+ and axon degeneration revisited: Nmnat1 cannot substitute for WldS to delay Wallerian degeneration. Cell Death Differ. 14, 116–127 (2007)

    Article  CAS  Google Scholar 

  14. Araki, T., Sasaki, Y. & Milbrandt, J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305, 1010–1013 (2004)

    Article  CAS  ADS  Google Scholar 

  15. Wang, J. et al. A local mechanism mediates NAD-dependent protection of axon degeneration. J. Cell Biol. 170, 349–355 (2005)

    Article  CAS  Google Scholar 

  16. Tsuda, H. et al. The AXH domain of ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins. Cell 122, 633–644 (2005)

    Article  CAS  Google Scholar 

  17. Cummings, C. J. et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nature Genet. 19, 148–154 (1998)

    Article  CAS  Google Scholar 

  18. Cummings, C. J. et al. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum. Mol. Genet. 10, 1511–1518 (2001)

    Article  CAS  Google Scholar 

  19. Sun, B., Xu, P. & Salvaterra, P. M. Dynamic visualization of nervous system in live Drosophila. Proc. Natl Acad. Sci. USA 96, 10438–10443 (1999)

    Article  CAS  ADS  Google Scholar 

  20. Parsell, D. A., Kowal, A. S., Singer, M. A. & Lindquist, S. Protein disaggregation mediated by heat-shock protein Hsp104. Nature 372, 475–478 (1994)

    Article  CAS  ADS  Google Scholar 

  21. Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998)

    Article  CAS  ADS  Google Scholar 

  22. Chang, Z. et al. Mycobacterium tuberculosis 16-kDa antigen (Hsp16.3) functions as an oligomeric structure in vitro to suppress thermal aggregation. J. Biol. Chem. 271, 7218–7223 (1996)

    Article  CAS  Google Scholar 

  23. Kubo, Y. et al. Two distinct mechanisms operate in the reactivation of heat-denatured proteins by the mitochondrial Hsp70/Mdj1p/Yge1p chaperone system. J. Mol. Biol. 286, 447–464 (1999)

    Article  CAS  Google Scholar 

  24. Holm, L. & Sander, C. New structure–novel fold? Structure 5, 165–171 (1997)

    Article  CAS  Google Scholar 

  25. Zhang, X. et al. Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis. J. Biol. Chem. 278, 13503–13511 (2003)

    Article  CAS  Google Scholar 

  26. Sousa, M. C. & McKay, D. B. Structure of the universal stress protein of Haemophilus influenzae. Structure 9, 1135–1141 (2001)

    Article  CAS  Google Scholar 

  27. Li, J. & Sha, B. Crystal structure of the E. coli Hsp100 ClpB N-terminal domain. Structure 11, 323–328 (2003)

    Article  CAS  Google Scholar 

  28. Lim, J. et al. A protein–protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 125, 801–814 (2006)

    Article  CAS  Google Scholar 

  29. Jia, H. et al. Identification of a critical site in Wld(s): essential for Nmnat enzyme activity and axon-protective function. Neurosci. Lett. 413, 46–51 (2007)

    Article  CAS  Google Scholar 

  30. Michels, A. A. et al. Hsp70 and Hsp40 chaperone activities in the cytoplasm and the nucleus of mammalian cells. J. Biol. Chem. 272, 33283–33289 (1997)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Zoghbi and R. Morimoto for reagents. We thank H. Zoghbi, H. Gilbert, H.-C. Lu, X. Zhou, P. Tsoulfas and A. Malhotra for technical suggestions and discussions. We also thank G. McNamara and the Analytical Imaging Core Facility at the University of Miami for imaging assistance. Some confocal imaging was supported by the BCM Mental Retardation and Developmental Disabilities Research Center. R.G.Z., P.R.H., C.M.H. were supported by the HHMI. H.J.B. is an HHMI investigator. R.G.Z. and F.Z. are also supported by the PhRMA Foundation and the Florida Department of Health, James and Esther King Biomedical Research Program.

Author Contributions R.G.Z. and H.J.B. conceived the experiments. R.G.Z., P.R.H., Y.C. and C.M.H. performed the genetic and in vivo experiments. R.G.Z. and F.Z. performed the in vitro experiments. R.G.Z. and H.J.B. wrote the manuscript.

Author information

Author notes

  1. P. Robin Hiesinger

    Present address: Present address: Department of Physiology and Green Center Division for Systems Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.,

  2. R. Grace Zhai and Fan Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA,

    R. Grace Zhai & Fan Zhang

  2. Howard Hughes Medical Institute, Baylor College of Medicine,,

    R. Grace Zhai, P. Robin Hiesinger, Claire M. Haueter & Hugo J. Bellen

  3. Department of Molecular and Human Genetics, Baylor College of Medicine,

    R. Grace Zhai, Yu Cao & Hugo J. Bellen

  4. Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA,

    Hugo J. Bellen

Authors
  1. R. Grace Zhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Robin Hiesinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claire M. Haueter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hugo J. Bellen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to R. Grace Zhai or Hugo J. Bellen.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-6 with Legends. (PDF 1657 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhai, R., Zhang, F., Hiesinger, P. et al. NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature 452, 887–891 (2008). https://doi.org/10.1038/nature06721

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06721

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing