Skip to main content
SpringerLink
Log in

Distinct conformers of transmissible misfolded SOD1 distinguish human SOD1-FALS from other forms of familial and sporadic ALS

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Evidence of misfolded wild-type superoxide dismutase 1 (SOD1) has been detected in spinal cords of sporadic ALS (sALS) patients, suggesting an etiological relationship to SOD1-associated familial ALS (fALS). Given that there are currently a number of promising therapies under development that target SOD1, it is of critical importance to better understand the role of misfolded SOD1 in sALS. We previously demonstrated the permissiveness of the G85R-SOD1:YFP mouse model for MND induction following injection with tissue homogenates from paralyzed transgenic mice expressing SOD1 mutations. This prompted us to examine whether WT SOD1 can self-propagate misfolding of the G85R-SOD1:YFP protein akin to what has been observed with mutant SOD1. Using the G85R-SOD1:YFP mice, we demonstrate that misfolded conformers of recombinant WT SOD1, produced in vitro, induce MND with a distinct inclusion pathology. Furthermore, the distinct pathology remains upon successive passages in the G85R-SOD1:YFP mice, strongly supporting the notion for conformation-dependent templated propagation and SOD1 strains. To determine the presence of a similar misfolded WT SOD1 conformer in sALS tissue, we screened homogenates from patients diagnosed with sALS, fALS, and non-ALS disease in an organotypic spinal cord slice culture assay. Slice cultures from G85R-SOD1:YFP mice exposed to spinal homogenates from patients diagnosed with ALS caused by the A4V mutation in SOD1 developed robust inclusion pathology, whereas spinal homogenates from more than 30 sALS cases and various controls failed. These findings suggest that mutant SOD1 has prion-like attributes that do not extend to SOD1 in sALS tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Aguzzi A, Heikenwalder M, Polymenidou M (2007) Insights into prion strains and neurotoxicity. Nat Rev Mol Cell Biol 8:552–561. doi:10.1038/nrm2204

    Article  CAS  PubMed  Google Scholar 

  2. Ayers J, Fromholt S, Koch M, DeBosier A, McMahon B, Xu G, Borchelt DR (2014) Experimental transmissibility of mutant SOD1 motor neuron disease. Acta Neuropathol 128:791–803. doi:10.1007/s00401-014-1342-7

    Article  CAS  PubMed  Google Scholar 

  3. Ayers J, Fromholt SE, O’Neal VM, Diamond JH, Borchelt DR (2016) Prion-like propagation of mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical pathways. Acta Neuropathol 131:103–114. doi:10.1007/s00401-015-1514-0

    Article  CAS  PubMed  Google Scholar 

  4. Ayers J, Xu G, Pletnikova O, Troncoso JC, Hart PJ, Borchelt DR (2014) Conformational specificity of the C4F6 SOD1 antibody; low frequency of reactivity in sporadic ALS cases. Acta Neuropathol Commun 2:55. doi:10.1186/2051-5960-2-55

    Article  PubMed  PubMed Central  Google Scholar 

  5. Banci L, Bertini I, Durazo A, Girotto S, Gralla EB, Martinelli M, Valentine JS, Vieru M, Whitelegge JP (2007) Metal-free superoxide dismutase forms soluble oligomers under physiological conditions: a possible general mechanism for familial ALS. Proc Natl Acad Sci USA 104:11263–11267. doi:10.1073/pnas.0704307104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bessen RA, Marsh RF (1992) Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters. J Gen Virol 73(Pt 2):329–334

    Article  PubMed  Google Scholar 

  7. Bidhendi EE, Bergh J, Zetterström P, Andersen PM, Marklund SL, Brännström T (2016) Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis–like disease. J Clin Invest. doi:10.1172/JCI84360

    PubMed  PubMed Central  Google Scholar 

  8. Bosco DA, Morfini G, Karabacak NM, Song Y, Gros-Louis F, Pasinelli P, Goolsby H, Fontaine BA, Lemay N, McKenna-Yasek D, Frosch MP, Agar JN, Julien J-P, Brady ST, Brown RH (2010) Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci 13:1396–1403. doi:10.1038/nn.2660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Brotherton TE, Li Y, Cooper D, Gearing M, Julien J-P, Rothstein JD, Boylan K, Glass JD (2012) Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS. Proc Natl Acad Sci USA. doi:10.1073/pnas.1115009109

    PubMed  PubMed Central  Google Scholar 

  10. Bruce M, Chree A, McConnell I, Foster J, Pearson G, Fraser H (1994) Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier. Philos Trans R Soc Lond B Biol Sci 343:405–411. doi:10.1098/rstb.1994.0036

    Article  CAS  PubMed  Google Scholar 

  11. Cao X, Antonyuk SV, Seetharaman SV, Whitson LJ, Taylor AB, Holloway SP, Strange RW, Doucette PA, Valentine JS, Tiwari A, Hayward LJ, Padua S, Cohlberg JA, Hasnain SS, Hart PJ (2008) Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis. J Biol Chem 283:16169–16177. doi:10.1074/jbc.M801522200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chattopadhyay M, Durazo A, Sohn SH, Strong CD, Gralla EB, Whitelegge JP, Valentine JS (2008) Initiation and elongation in fibrillation of ALS-linked superoxide dismutase. Proc Natl Acad Sci USA 105:18663–18668. doi:10.1073/pnas.0807058105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chia R, Tattum MH, Jones S, Collinge J, Fisher EMC, Jackson GS (2010) Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis. PLoS One 5:e10627. doi:10.1371/journal.pone.0010627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Deng H-X, Shi Y-Z, Furukawa Y, Zhai H, Fu R, Liu E, Gorrie GH, Khan MS, Hung W-Y, Bigio EH, Lukas T, Dal Canto MC, O’Halloran TV, Siddique T (2006) Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proc Natl Acad Sci USA 103:7142–7147. doi:10.1073/pnas.0602046103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dickinson AG, Meikle VM (1971) Host-genotype and agent effects in scrapie incubation: change in allelic interaction with different strains of agent. Mol Gen Genet 112:73–79

    Article  CAS  PubMed  Google Scholar 

  16. Ezzi SA, Urushitani M, Julien J-P (2007) Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation. J Neurochem 102:170–178. doi:10.1111/j.1471-4159.2007.04531.x

    Article  CAS  PubMed  Google Scholar 

  17. Forsberg K, Jonsson PA, Andersen PM, Bergemalm D, Graffmo KS, Hultdin M, Jacobsson J, Rosquist R, Marklund SL, Brännström T (2010) Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients. PLoS One 5:e11552. doi:10.1371/journal.pone.0011552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fraser H, Dickinson AG (1968) The sequential development of the brain lesion of scrapie in three strains of mice. J Comp Pathol 78:301–311

    Article  CAS  PubMed  Google Scholar 

  19. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM-Y (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533

    Article  CAS  PubMed  Google Scholar 

  20. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934. doi:10.1016/j.cell.2010.02.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Goldfarb LG, Petersen RB, Tabaton M, Brown P, LeBlanc AC, Montagna P, Cortelli P, Julien J, Vital C, Pendelbury WW (1992) Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science 258:806–808

    Article  CAS  PubMed  Google Scholar 

  22. Grad LI, Yerbury JJ, Turner BJ, Guest WC, Pokrishevsky E, O’Neill MA, Yanai A, Silverman JM, Zeineddine R, Corcoran L, Kumita JR, Luheshi LM, Yousefi M, Coleman BM, Hill AF, Plotkin SS, Mackenzie IR, Cashman NR (2014) Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc Natl Acad Sci USA 111:3620–3625. doi:10.1073/pnas.1312245111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Graffmo KS, Forsberg K, Bergh J, Birve A, Zetterstrom P, Andersen PM, Marklund SL, Brannstrom T (2012) Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis. Hum Mol Genet 22:51–60. doi:10.1093/hmg/dds399

    Article  CAS  PubMed  Google Scholar 

  24. Jaarsma D, Rognoni F, van Duijn W, Verspaget HW, Haasdijk ED, Holstege JC (2001) CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol 102:293–305. doi:10.1007/s004010100399

    CAS  PubMed  Google Scholar 

  25. Kerman A, Liu H-N, Croul S, Bilbao J, Rogaeva E, Zinman L, Robertson J, Chakrabartty A (2010) Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form. Acta Neuropathol 119:335–344. doi:10.1007/s00401-010-0646-5

    Article  PubMed  Google Scholar 

  26. Kovács GG, Trabattoni G, Hainfellner JA, Ironside JW, Knight RSG, Budka H (2002) Mutations of the prion protein gene phenotypic spectrum. J Neurol 249:1567–1582. doi:10.1007/s00415-002-0896-9

    Article  CAS  PubMed  Google Scholar 

  27. Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405. doi:10.1038/78078

    Article  CAS  PubMed  Google Scholar 

  28. Münch C, O’Brien J, Bertolotti A (2011) Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci USA 108:3548–3553. doi:10.1073/pnas.1017275108

    Article  PubMed  PubMed Central  Google Scholar 

  29. Peretz D, Scott MR, Groth D, Williamson RA, Burton DR, Cohen FE, Prusiner SB (2001) Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci 10:854–863. doi:10.1110/ps.39201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pokrishevsky E, Grad LI, Yousefi M, Wang J, Mackenzie IR, Cashman NR (2012) Aberrant localization of FUS and TDP43 is associated with misfolding of SOD1 in amyotrophic lateral sclerosis. PLoS One 7:e35050. doi:10.1371/journal.pone.0035050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Prudencio M, Durazo A, Whitelegge JP, Borchelt DR (2010) An examination of wild-type SOD1 in modulating the toxicity and aggregation of ALS-associated mutant SOD1. Hum Mol Genet 19:4774–4789. doi:10.1093/hmg/ddq408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Prudencio M, Hart PJ, Borchelt DR, Andersen PM (2009) Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. Hum Mol Genet 18:3217–3226. doi:10.1093/hmg/ddp260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rakhit R, Crow JP, Lepock JR, Kondejewski LH, Cashman NR, Chakrabartty A (2004) Monomeric Cu, Zn-superoxide dismutase is a common misfolding intermediate in the oxidation models of sporadic and familial amyotrophic lateral sclerosis. J Biol Chem 279:15499–15504. doi:10.1074/jbc.M313295200

    Article  CAS  PubMed  Google Scholar 

  34. Rakhit R, Cunningham P, Furtos-Matei A, Dahan S, Qi X-F, Crow JP, Cashman NR, Kondejewski LH, Chakrabartty A (2002) Oxidation-induced misfolding and aggregation of superoxide dismutase and its implications for amyotrophic lateral sclerosis. J Biol Chem 277:47551–47556. doi:10.1074/jbc.M207356200

    Article  CAS  PubMed  Google Scholar 

  35. Reed LJ, Muench H (1938) A simple method of estimating fifty per cent endpoints. Am J Epidemiol 27:493–497

    Google Scholar 

  36. Seetharaman SV, Taylor AB, Holloway S, Hart PJ (2010) Structures of mouse SOD1 and human/mouse SOD1 chimeras. Arch Biochem Biophys 503:183–190. doi:10.1016/j.abb.2010.08.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang J, Farr GW, Zeiss CJ, Rodriguez-Gil DJ, Wilson JH, Furtak K, Rutkowski DT, Kaufman RJ, Ruse CI, Yates JR, Perrin S, Feany MB, Horwich AL (2009) Progressive aggregation despite chaperone associations of a mutant SOD1-YFP in transgenic mice that develop ALS. Proc Natl Acad Sci USA 106:1392–1397. doi:10.1073/pnas.0813045106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang J, Xu G, Li H, Gonzales V, Fromholt D, Karch CM, Copeland NG, Jenkins NA, Borchelt DR (2005) Somatodendritic accumulation of misfolded SOD1-L126Z in motor neurons mediates degeneration: alphaB-crystallin modulates aggregation. Hum Mol Genet 14:2335–2347. doi:10.1093/hmg/ddi236

    Article  CAS  PubMed  Google Scholar 

  39. Xu G, Ayers J, Roberts BL, Brown H, Fromholt S, Green C, Borchelt DR (2014) Direct and indirect mechanisms for wild-type SOD1 to enhance the toxicity of mutant SOD1 in bigenic transgenic mice. Hum Mol Genet. doi:10.1093/hmg/ddu517

    Google Scholar 

  40. Zetterström P, Stewart HG, Bergemalm D, Jonsson PA, Graffmo KS, Andersen PM, Brännström T, Oliveberg M, Marklund SL (2007) Soluble misfolded subfractions of mutant superoxide dismutase-1 s are enriched in spinal cords throughout life in murine ALS models. Proc Natl Acad Sci USA 104:14157–14162. doi:10.1073/pnas.0700477104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We would like to thank the patients and family members who contributed tissue to the study; Drs. B. Giasson and J. Lewis for donating mouse tissue for the study; and Dr. C. Janus for his help on statistical analysis. A. G. was supported by St. Mary’s University Research Grant and the Biaggini Research Program. This work was supported by an NIH Shared Instrumentation Grant (S10OD020026), a grant from the National Institutes of Neurological Disease and Stroke (1R01NA092788-01), and the Packard Center for ALS Research at Johns Hopkins University. Collection and characterization of human tissues provided by Johns Hopkins were funded by the Target ALS Multicenter Post-mortem Tissue Core.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Box 100159, Gainesville, FL, 32610, USA

    Jacob I. Ayers, Jeffrey Diamond, Adriana Sari, Susan Fromholt & David R. Borchelt

  2. SantaFe HealthCare Alzheimer’s Disease Research Center, McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA

    David R. Borchelt

  3. Department of Biological Sciences, St. Mary’s University, San Antonio, TX, 78228, USA

    Ahmad Galaleldeen & P. John Hart

  4. Department of Biochemistry and X-ray Crystallography Core Laboratory, University of Texas Health Science Center, San Antonio, TX, 78229, USA

    Ahmad Galaleldeen

  5. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Lyle W. Ostrow

  6. Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Jonathan D. Glass

  7. Department of Veterans Affairs, Geriatric Research, Education, and Clinical Center, South Texas Health Care System, San Antonio, TX, 78229, USA

    P. John Hart

Authors
  1. Jacob I. Ayers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey Diamond
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adriana Sari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan Fromholt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahmad Galaleldeen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lyle W. Ostrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jonathan D. Glass
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P. John Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David R. Borchelt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jacob I. Ayers.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ayers, J.I., Diamond, J., Sari, A. et al. Distinct conformers of transmissible misfolded SOD1 distinguish human SOD1-FALS from other forms of familial and sporadic ALS. Acta Neuropathol 132, 827–840 (2016). https://doi.org/10.1007/s00401-016-1623-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-016-1623-4

Keywords

Search

Navigation