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:

Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP

Nature Genetics volume 37, pages 974–979 (2005)Cite this article

Abstract

Endoplasmic reticulum (ER) chaperones and ER stress have been implicated in the pathogenesis of neurodegenerative disorders, such as Alzheimer and Parkinson diseases, but their contribution to neuron death remains uncertain1,2. In this study, we establish a direct in vivo link between ER dysfunction and neurodegeneration. Mice homozygous with respect to the woozy (wz) mutation develop adult-onset ataxia with cerebellar Purkinje cell loss. Affected cells have intracellular protein accumulations reminiscent of protein inclusions in both the ER and the nucleus. In addition, upregulation of the unfolded protein response, suggestive of ER stress, occurs in mutant Purkinje cells. We report that the wz mutation disrupts the gene Sil1 that encodes an adenine nucleotide exchange factor of BiP3, a crucial ER chaperone4. These findings provide evidence that perturbation of ER chaperone function in terminally differentiated neurons leads to protein accumulation, ER stress and subsequent neurodegeneration.

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: Purkinje neuron degeneration in the woozy mutant cerebellum.
Figure 2: Identification of Sil1 as the wz locus.
Figure 3: The wz mutation results in formation of protein accumulations in Purkinje cells.
Figure 4: Localization of protein accumulations in Purkinje cells.
Figure 5: Truncation of Sil1 induces the ER stress response.
Figure 6: ER stress response in wz Purkinje cells.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Nakagawa, T. et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98–103 (2000).

    Article  CAS  Google Scholar 

  2. Imai, Y. et al. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891–902 (2001).

    Article  CAS  Google Scholar 

  3. Chung, K.T., Shen, Y. & Hendershot, L.M. BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP. J. Biol. Chem. 277, 47557–47563 (2002).

    Article  CAS  Google Scholar 

  4. Rose, M.D., Misra, L.M. & Vogel, J.P. KAR2, a karyogamy gene, is the yeast homolog of the mammalian BiP/GRP78 gene. Cell 57, 1211–1221 (1989).

    Article  CAS  Google Scholar 

  5. Selkoe, D.J. Folding proteins in fatal ways. Nature 426, 900–904 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Warrick, J.M. et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat. Genet. 23, 425–428 (1999).

    Article  CAS  Google Scholar 

  8. Southwood, C.M., Garbern, J., Jiang, W. & Gow, A. The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher disease. Neuron 36, 585–596 (2002).

    Article  CAS  Google Scholar 

  9. Larsen, K.E. & Sulzer, D. Autophagy in neurons: a review. Histol. Histopathol. 17, 897–908 (2002).

    CAS  PubMed  Google Scholar 

  10. Skarnes, W.C., Moss, J.E., Hurtley, S.M. & Beddington, R.S. Capturing genes encoding membrane and secreted proteins important for mouse development. Proc. Natl. Acad. Sci. USA 92, 6592–6596 (1995).

    Article  CAS  Google Scholar 

  11. Tyson, J.R. & Stirling, C.J. LHS1 and SIL1 provide a lumenal function that is essential for protein translocation into the endoplasmic reticulum. EMBO J. 19, 6440–6452 (2000).

    Article  CAS  Google Scholar 

  12. Gething, M.J. Role and regulation of the ER chaperone BiP. Semin. Cell Dev. Biol. 10, 465–472 (1999).

    Article  CAS  Google Scholar 

  13. Kabani, M., Beckerich, J.M. & Gaillardin, C. Sls1p stimulates Sec63p-mediated activation of Kar2p in a conformation-dependent manner in the yeast endoplasmic reticulum. Mol. Cell. Biol. 20, 6923–6934 (2000).

    Article  CAS  Google Scholar 

  14. Ross, C.A. & Pickart, C.M. The ubiquitin-proteasome pathway in Parkinson's disease and other neurodegenerative diseases. Trends Cell Biol. 14, 703–711 (2004).

    Article  CAS  Google Scholar 

  15. Ron, D. Translational control in the endoplasmic reticulum stress response. J. Clin. Invest. 110, 1383–1388 (2002).

    Article  CAS  Google Scholar 

  16. Ma, Y. & Hendershot, L.M. The unfolding tale of the unfolded protein response. Cell 107, 827–830 (2001).

    Article  CAS  Google Scholar 

  17. Zhang, K. & Kaufman, R.J. Signaling the unfolded protein response from the endoplasmic reticulum. J. Biol. Chem. 279, 25935–25938 (2004).

    Article  CAS  Google Scholar 

  18. Kimata, Y. et al. Genetic evidence for a role of BiP/Kar2 that regulates Ire1 in response to accumulation of unfolded proteins. Mol. Biol. Cell 14, 2559–2569 (2003).

    Article  CAS  Google Scholar 

  19. Lee, A.S. The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem. Sci. 26, 504–510 (2001).

    Article  CAS  Google Scholar 

  20. Wang, X.Z. et al. Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153). Mol. Cell. Biol. 16, 4273–4280 (1996).

    Article  CAS  Google Scholar 

  21. Zinszner, H. et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 12, 982–995 (1998).

    Article  CAS  Google Scholar 

  22. Lin, X., Antalffy, B., Kang, D., Orr, H.T. & Zoghbi, H.Y. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat. Neurosci. 3, 157–163 (2000).

    Article  CAS  Google Scholar 

  23. Altman, J. & Bayer, S.A. Development of the Cerebellar System: In Relation to its Evolution, Structure and Functions (CRC Press, Inc., Boca Raton, Florida, 1997).

    Google Scholar 

  24. Tessitore, A. et al. GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Mol. Cell 15, 753–766 (2004).

    Article  CAS  Google Scholar 

  25. Slemmer, J.E., De Zeeuw, C.I. & Weber, J.T. Don't get too excited: mechanisms of glutamate-mediated Purkinje cell death. Prog. Brain Res. 148, 367–390 (2005).

    Article  CAS  Google Scholar 

  26. Fletcher, C.F. et al. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell 87, 607–617 (1996).

    Article  CAS  Google Scholar 

  27. Kitao, Y. et al. ORP150/HSP12A regulates Purkinje cell survival: a role for endoplasmic reticulum stress in cerebellar development. J. Neurosci. 24, 1486–1496 (2004).

    Article  CAS  Google Scholar 

  28. Serra, H.G. et al. Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum. Mol. Genet. 13, 2535–2543 (2004).

    Article  CAS  Google Scholar 

  29. Ackerman, S.L. et al. The mouse rostral cerebellar malformation gene encodes an UNC-5-like protein. Nature 386, 838–842 (1997).

    Article  CAS  Google Scholar 

  30. Goldowitz, D., Hamre, K.M., Przyborski, S.A. & Ackerman, S.L. Granule cells and cerebellar boundaries: analysis of Unc5h3 mutant chimeras. J. Neurosci. 20, 4129–4137 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank The Jackson Laboratory sequencing facility, histology, microinjection and bioimaging services for their contributions; R. Bronson for assistance with electron microscopy; and L.L. Beverly-Staggs for technical assistance. We also thank BayGenomics, which is supported by the US National Heart, Lung, and Blood Institute. This study is supported by grants from the US National Institutes of Health (S.L.A) and a Mouse Mutant Resource grant from the US National Institutes of Health.

Author information

Authors and Affiliations

  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, 04609, Maine, USA

    Lihong Zhao, Chantal Longo-Guess, Belinda S Harris, Jeong-Woong Lee & Susan L Ackerman

  2. The Howard Hughes Medical Institute, Bar Harbor, 04609, Maine, USA

    Susan L Ackerman

Authors
  1. Lihong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chantal Longo-Guess
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Belinda S Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeong-Woong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Susan L Ackerman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susan L Ackerman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Co-localization of SIL1 and BiP. (PDF 850 kb)

Supplementary Fig. 2

SIL1 truncated by the wz mutation retains the ability to interact with BiP. (PDF 163 kb)

Supplementary Table 1

Primers used in Sil1 genomic and RT-PCR. (PDF 27 kb)

Supplementary Video 1

A four-month old CxB5/ByJ-woozy mutant mouse (wz/wz) and its wild type littermate (+/+) are shown. Note the tremors and truncal ataxia in the wz/wz mouse. (MOV 1368 kb)

Supplementary Methods (PDF 34 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, L., Longo-Guess, C., Harris, B. et al. Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Nat Genet 37, 974–979 (2005). https://doi.org/10.1038/ng1620

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1620

This article is cited by

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