Direct observation of prion-like propagation of protein misfolding templated by pathogenic mutants

Chiti, F. & Dobson, C. M. Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu. Rev. Biochem. 86, 27–68 (2017).Article 
CAS 
PubMed 

Google Scholar 
Colby, D. W. & Prusiner, S. B. Prions. Cold Spring Harb. Perspect. Biol. 3, a006833 (2011).Article 
PubMed 
PubMed Central 

Google Scholar 
McAlary, L., Plotkin, S. S., Yerbury, J. J. & Cashman, N. R. Prion-like propagation of protein misfolding and aggregation in amyotrophic lateral sclerosis. Front. Mol. Neurosci. 12, 262 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Vaquer-Alicea, J. & Diamond, M. I. Propagation of protein aggregation in neurodegenerative diseases. Annu. Rev. Biochem. 88, 785–810 (2019).Article 
CAS 
PubMed 

Google Scholar 
Jahn, T. R. & Radford, S. E. Folding versus aggregation: polypeptide conformations on competing pathways. Arch. Biochem. Biophys. 469, 100–117 (2008).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Yu, H. et al. Protein misfolding occurs by slow diffusion across multiple barriers in a rough energy landscape. Proc. Natl Acad. Sci. USA 112, 8308–8313 (2015).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Hoffmann, A., Neupane, K. & Woodside, M. T. Single-molecule assays for investigating protein misfolding and aggregation. Phys. Chem. Chem. Phys. 15, 7934–7948 (2013).Article 
CAS 
PubMed 

Google Scholar 
Wu, J., Cao, C., Loch, R. A., Tiiman, A. & Luo, J. Single-molecule studies of amyloid proteins: from biophysical properties to diagnostic perspectives. Q. Rev. Biophys. 53, e12 (2020).Article 
CAS 
PubMed 

Google Scholar 
Prudencio, M., Durazo, A., Whitelegge, J. P. & Borchelt, D. R. An examination of wild-type SOD1 in modulating the toxicity and aggregation of ALS-associated mutant SOD1. Hum. Mol. Genet. 19, 4774–4789 (2010).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Grad, L. I. et al. Intermolecular transmission of superoxide dismutase 1 misfolding in living cells. Proc. Natl Acad. Sci. USA 108, 16398–16403 (2011).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Woo, T.-G. et al. Novel chemical inhibitor against SOD1 misfolding and aggregation protects neuron-loss and ameliorates disease symptoms in ALS mouse model. Commun. Biol. 4, 1397 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Lindberg, M. J., Normark, J., Holmgren, A. & Oliveberg, M. Folding of human superoxide dismutase: Disulfide reduction prevents dimerization and produces marginally stable monomers. Proc. Natl Acad. Sci. USA 101, 15893–15898 (2004).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Lindberg, M. J., Byström, R., Boknäs, N., Andersen, P. M. & Oliveberg, M. Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants. Proc. Natl Acad. Sci. USA 102, 9754–9759 (2005).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Proctor, E. A., Ding, F. & Dokholyan, N. V. Structural and thermodynamic effects of post-translational modifications in mutant and wild type Cu, Zn superoxide dismutase. J. Mol. Biol. 408, 555–567 (2011).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Sen Mojumdar, S. et al. Partially native intermediates mediate misfolding of SOD1 in single-molecule folding trajectories. Nat. Commun. 8, 1881 (2017).Article 
PubMed 
PubMed Central 

Google Scholar 
Broom, H. R., Rumfeldt, J. A. O., Vassall, K. A. & Meiering, E. M. Destabilization of the dimer interface is a common consequence of diverse ALS-associated mutations in metal free SOD1. Protein Sci. 24, 2081–2089 (2015).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Hörnberg, A., Logan, D. T., Marklund, S. L. & Oliveberg, M. The coupling between disulphide status, metallation and dimer interface strength in Cu/Zn superoxide dismutase. J. Mol. Biol. 365, 333–342 (2007).Article 
PubMed 

Google Scholar 
Petrosyan, R., Narayan, A. & Woodside, M. T. Single-molecule force spectroscopy of protein folding. J. Mol. Biol. 433, 167207 (2021).Article 
CAS 
PubMed 

Google Scholar 
Furukawa, Y. & O’Halloran, T. V. Amyotrophic lateral sclerosis mutations have the greatest destabilizing effect on the apo- and reduced form of SOD1, leading to unfolding and oxidative aggregation. J. Biol. Chem. 280, 17266–17274 (2005).Article 
CAS 
PubMed 

Google Scholar 
Oztug Durer, Z. A. et al. Loss of metal ions, disulfide reduction and mutations related to familial ALS promote formation of amyloid-like aggregates from superoxide dismutase. PLoS ONE 4, e5004 (2009).Article 
PubMed 
PubMed Central 

Google Scholar 
Andersen, P. M. et al. Phenotypic heterogeneity in motor neuron disease patients with CuZn–superoxide dismutase mutations in Scandinavia. Brain 120, 1723–1737 (1997).Article 
PubMed 

Google Scholar 
Juneja, T., Pericak-Vance, M. A., Laing, N. G., Dave, S. & Siddique, T. Prognosis in familial amyotrophic lateral sclerosis. Neurology 48, 55–57 (1997).Article 
CAS 
PubMed 

Google Scholar 
Rodriguez, J. A. et al. Familial amyotrophic lateral sclerosis-associated mutations decrease the thermal stability of distinctly metallated species of human copper/zinc superoxide dismutase. J. Biol. Chem. 277, 15932–15937 (2002).Article 
CAS 
PubMed 

Google Scholar 
Borchelt, D. R. et al. Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc. Natl Acad. Sci. USA 91, 8292–8296 (1994).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Jonsson, P. A. et al. Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis. Brain 127, 73–88 (2004).Article 
PubMed 

Google Scholar 
Weydert, C. J. & Cullen, J. J. Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nat. Protoc. 5, 51–66 (2010).Article 
CAS 
PubMed 

Google Scholar 
Rakhit, R. et al. An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS. Nat. Med. 13, 754–759 (2007).Article 
CAS 
PubMed 

Google Scholar 
Atlasi, R. S. et al. Investigation of anti-SOD1 antibodies yields new structural insight into SOD1 misfolding and surprising behavior of the antibodies themselves. ACS Chem. Biol. 13, 2794–2807 (2018).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Asor, R. & Kukura, P. Characterising biomolecular interactions and dynamics with mass photometry. Curr. Opin. Chem. Biol. 68, 102132 (2022).Article 
CAS 
PubMed 

Google Scholar 
Meisl, G., Knowles, T. P. & Klenerman, D. The molecular processes underpinning prion-like spreading and seed amplification in protein aggregation. Curr. Opin. Neurobiol. 61, 58–64 (2020).Article 
CAS 
PubMed 

Google Scholar 
Griffith, J. S. Nature of the scrapie agent: self-replication and scrapie. Nature 215, 1043–1044 (1967).Article 
CAS 
PubMed 

Google Scholar 
Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).Article 
CAS 
PubMed 

Google Scholar 
Scialò, C., De Cecco, E., Manganotti, P. & Legname, G. Prion and prion-like protein strains: deciphering the molecular basis of heterogeneity in neurodegeneration. Viruses 11, 261 (2019).Article 
PubMed 
PubMed Central 

Google Scholar 
Soto, C. & Pritzkow, S. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat. Neurosci. 21, 1332–1340 (2018).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Li, J., Browning, S., Mahal, S. P., Oelschlegel, A. M. & Weissmann, C. Darwinian evolution of prions in cell culture. Science 327, 869–872 (2010).Article 
CAS 
PubMed 

Google Scholar 
Bergh, J. et al. Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping. Proc. Natl Acad. Sci. USA 112, 4489–4494 (2015).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Sekhar, A. et al. Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways. eLife 4, e07296 (2015).Article 
PubMed 
PubMed Central 

Google Scholar 
Luchinat, E. et al. In-cell NMR reveals potential precursor of toxic species from SOD1 fALS mutants. Nat. Commun. 5, 5502 (2014).Article 
CAS 
PubMed 

Google Scholar 
Stevens, J. C. et al. Modification of superoxide dismutase 1 (SOD1) properties by a GFP tag–implications for research into amyotrophic lateral sclerosis (ALS). PLoS ONE 5, e9541 (2010).Article 
PubMed 
PubMed Central 

Google Scholar 
Rotunno, M. S. et al. Identification of a misfolded region in superoxide dismutase 1 that is exposed in amyotrophic lateral sclerosis. J. Biol. Chem. 289, 28527–28538 (2014).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Bruns, C. K. & Kopito, R. R. Impaired post-translational folding of familial ALS-linked Cu, Zn superoxide dismutase mutants. EMBO J. 26, 855–866 (2007).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Crown, A. et al. Tryptophan residue 32 in human Cu–Zn superoxide dismutase modulates prion-like propagation and strain selection. PLoS ONE 15, e0227655 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Gupta, A. N. et al. Pharmacological chaperone reshapes the energy landscape for folding and aggregation of the prion protein. Nat. Commun. 7, 12058 (2016).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Mashaghi, A., Kramer, G., Lamb, D. C., Mayer, M. P. & Tans, S. J. Chaperone action at the single-molecule level. Chem. Rev. 114, 660–676 (2014).Article 
CAS 
PubMed 

Google Scholar 
Mitsumoto, H. et al. Quantitative objective markers for upper and lower motor neuron dysfunction in ALS. Neurology 68, 1402–1410 (2007).Article 
CAS 
PubMed 

Google Scholar 
Walder, R. et al. Rapid characterization of a mechanically labile α-helical protein enabled by efficient site-specific bioconjugation. J. Am. Chem. Soc. 139, 9867–9875 (2017).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Liang, Y. & Fu, G. C. Catalytic asymmetric synthesis of tertiary alkyl fluorides: Negishi cross-couplings of racemic α,α-dihaloketones. J. Am. Chem. Soc. 136, 5520–5524 (2014).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Neuman, K. C. & Block, S. M. Optical trapping. Rev. Sci. Instrum. 75, 2787–2809 (2004).Article 
CAS 
PubMed 

Google Scholar 
Wang, M. D., Yin, H., Landick, R., Gelles, J. & Block, S. M. Stretching DNA with optical tweezers. Biophys. J. 72, 1335–1346 (1997).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Paul, S. S., Lyons, A., Kirchner, R. & Woodside, M. T. Quantifying oligomer populations in real time during protein aggregation using single-molecule mass photometry. ACS Nano 16, 16462–16470 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Neupane, K., Narayan, A., Sen Mojumdar, S. & Woodside, M.T. Single-molecule force spectroscopy data for prion-like conversion of wild-type SOD1 by pathogenic mutants G127X and G85R. Figshare https://doi.org/10.6084/m9.figshare.25751289

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