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Misfolded SOD1 is not a primary component of sporadic ALS

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Abstract

A common feature of inherited and sporadic ALS is accumulation of abnormal proteinaceous inclusions in motor neurons and glia. SOD1 is the major protein component accumulating in patients with SOD1 mutations, as well as in mutant SOD1 mouse models. ALS-linked mutations of SOD1 have been shown to increase its propensity to misfold and/or aggregate. Antibodies specific for monomeric or misfolded SOD1 have detected misfolded SOD1 accumulating predominantly in spinal cord motor neurons of ALS patients with SOD1 mutations. We now use seven different conformationally sensitive antibodies to misfolded human SOD1 (including novel high affinity antibodies currently in pre-clinical development) coupled with immunohistochemistry, immunofluorescence and immunoprecipitation to test for the presence of misfolded SOD1 in high quality human autopsy samples. Whereas misfolded SOD1 is readily detectable in samples from patients with SOD1 mutations, it is below detection limits for all of our measures in spinal cord and cortex tissues from patients with sporadic or non-SOD1 inherited ALS. The absence of evidence for accumulated misfolded SOD1 supports a conclusion that SOD1 misfolding is not a primary component of sporadic ALS.

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Acknowledgements

We thank Drs. Neil Cashman, Leslie Grad and Megan O’Neill (University of British Columbia, Vancouver) for providing us with the DSE2 3H1 and 10E11 misfolded SOD1 and for allowing SDC to visit his lab to compare immunoprecipitation methods in human patient samples from JR’s and NC’s banks. We thank Drs. Alexander McCampbell, Fang Qian and Paul Weinreb at Biogen (Cambridge, MA) for providing us with the 4A1 and A5E5 antibodies; and Drs. Thomas Brännström and Stefan Marklund (Umea University, Sweden) for their polyclonal 131-153Ra misfolded SOD1 antibody. This work was supported by the ALS Association (Grant ALSA 2006 to DWC) and NIH Grant R01-NS27036 to DWC. SDC and DWC received salary support from the Ludwig Institute for Cancer Research and JR from ALSA and NINDS.

Author information

Author notes

  1. Philippe A. Parone

    Present address: Fate Therapeutics, 3535 General Atomics Court, San Diego, CA, 92121, USA

  2. A. Bui, S. Saberi, S. K. Lee, J. Stauffer contributed equally to this work.

Authors and Affiliations

  1. Laboratory for Cell Biology, Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA

    Sandrine Da Cruz, Anh Bui, Sandra K. Lee, Melissa McAlonis-Downes, Philippe A. Parone & Don W. Cleveland

  2. Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Don W. Cleveland

  3. Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA

    Shahram Saberi, Jennifer Stauffer, Derek Schulte, Don W. Cleveland & John Ravits

  4. Department of Pathology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Donald P. Pizzo

Authors
  1. Sandrine Da Cruz
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  2. Anh Bui
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  3. Shahram Saberi
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  4. Sandra K. Lee
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  5. Jennifer Stauffer
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  6. Melissa McAlonis-Downes
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  7. Derek Schulte
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  8. Donald P. Pizzo
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  9. Philippe A. Parone
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  10. Don W. Cleveland
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  11. John Ravits
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Contributions

SDC, PAP, DWC and JR designed the experiments and analyzed the data. SDC, PAP, AB, SS, SKL, JS, DP, DS performed the experiments. SDC, DWC and JR wrote the manuscript. MMD provided reagents.

Corresponding authors

Correspondence to Don W. Cleveland or John Ravits.

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Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants and animals were in accordance with the ethical standards of the institution at which the studies were conducted.

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Da Cruz, S., Bui, A., Saberi, S. et al. Misfolded SOD1 is not a primary component of sporadic ALS. Acta Neuropathol 134, 97–111 (2017). https://doi.org/10.1007/s00401-017-1688-8

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  • DOI: https://doi.org/10.1007/s00401-017-1688-8

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