Characterization of Pairs of Toxic and Nontoxic Misfolded Protein Oligomers Elucidates the Structural Determinants of Oligomer Toxicity in Protein Misfolding Diseases
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High Resolution Image Download MS PowerPoint Slide Conspectus The aberrant misfolding and aggregation of peptides and proteins into amyloid aggregates occurs in over 50 largely incurable protein misfolding diseases. These pathologies include Alzheimer’s and Parkinson’s diseases, which are global medical emergencies owing to their prevalence in increasingly aging populations worldwide. Although the presence of mature amyloid aggregates is a hallmark of such neurodegenerative diseases, misfolded protein oligomers are increasingly recognized as of central importance in the pathogenesis of many of these maladies. These oligomers are small, diffusible species that can form as intermediates in the amyloid fibril formation process or be released by mature fibrils after they are formed. They have been closely associated with the induction of neuronal dysfunction and cell death. It has proven rather challenging to study these oligomeric species because of their short lifetimes, low concentrations, extensive structural heterogeneity, and challenges associated with producing stable, homogeneous, and reproducible populations. Despite these difficulties, investigators have developed protocols to produce kinetically, chemically, or structurally stabilized homogeneous populations of protein misfolded oligomers from several amyloidogenic peptides and proteins at experimentally ameneable concentrations. Furthermore, procedures have been established to produce morphologically similar but structurally distinct oligomers from the same protein sequence that are either toxic or nontoxic to cells. These tools offer unique opportunities to identify and investigate the structural determinants of oligomer toxicity by a close comparative inspection of their structures and the mechanisms of action through which they cause cell dysfunction. This Account reviews multidisciplinary results, including from our own groups, obtained by combining chemistry, physics, biochemistry, cell biology, and animal models for pairs of toxic and nontoxic oligomers. We describe oligomers comprised of the amyloid-β peptide, which underlie Alzheimer’s disease, and α-synuclein, which are associated with Parkinson’s disease and other related neurodegenerative pathologies, collectively known as synucleinopathies. Furthermore, we also discuss oligomers formed by the 91-residue N-terminal domain of [NiFe]-hydrogenase maturation factor from E. coli, which we use as a model non-disease-related protein, and by an amyloid stretch of Sup35 prion protein from yeast. These oligomeric pairs have become highly useful experimental tools for studying the molecular determinants of toxicity characteristic of protein misfolding diseases. Key properties have been identified that differentiate toxic from nontoxic oligomers in their ability to induce cellular dysfunction. These characteristics include solvent-exposed hydrophobic regions, interactions with membranes, insertion into lipid bilayers, and disruption of plasma membrane integrity. By using these properties, it has been possible to rationalize in model systems the responses to pairs of toxic and nontoxic oligomers. Collectively, these studies provide guidance for the development of efficacious therapeutic strategies to target rationally the cytotoxicity of misfolded protein oligomers in neurodegenerative conditions.
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Solvent-exposed hydrophobic residues appear to be a key shared property of toxic oligomers.
“In conclusion, solvent-exposed hydrophobic residues appear to be a key shared property of toxic oligomers [16].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [16]
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Cites
Lecanemab in early Alzheimer's disease
van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2212948 · Cited by 5,678 · see citing works
Protein folding and misfolding
Dobson, C. M. (2003) · Nature · doi:10.1038/nature02261 · Cited by 4,791 · see citing works
Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade
Chiti, F., & Dobson, C. M. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-045115 · Cited by 2,629 · see citing works
Self-citationThe proteostasis network and its decline in ageing
Hipp, M. S., Kasturi, P., & Hartl, F. U. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0101-y · Cited by 1,642 · see citing works
EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers
Ehrnhoefer, D. E., Bieschke, J., Boeddrich, A., Herbst, M., Masino, L., Lurz, R., Engemann, S., Pastore, A., & Wanker, E. (2008) · Nature Structural &Molecular Biology · doi:10.1038/nsmb.1437 · Cited by 1,424 · see citing works
Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein
Cremades, N., Cohen, S. I. A., Deas, E., Abramov, A. Y., Chen, A. Y., Orte, Á., Sandal, M., Clarke, R. W., Dunne, P., Aprile, F. A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.037 · Cited by 901 · see citing works
Self-citationThe Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
Cline, E. N., Bicca, M. A., Viola, K. L., & Klein, W. L. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179941 · Cited by 870 · see citing works
Buell, A. K., Galvagnion, C., Gaspar, R., Sparr, E., Vendruscolo, M., Knowles, T. P. J., Linse, S. S., & Dobson, C. M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315346111 · Cited by 666 · see citing works
Self-citationStructural basis of membrane disruption and cellular toxicity by α-synuclein oligomers
Fusco, G., Chen, S. W., Williamson, P. T. F., Cascella, R., Perni, M., Jarvis, J. A., Cecchi, C., Vendruscolo, M., Chiti, F., Cremades, N., et al. (2017) · Science · doi:10.1126/science.aan6160 · Cited by 665 · see citing works
Self-citationA causative link between the structure of aberrant protein oligomers and their toxicity
Campioni, S., Mannini, B., Zampagni, M., Pensalfini, A., Parrini, C., Evangelisti, E., Relini, A., Stefani, M., Dobson, C. M., Cecchi, C., et al. (2010) · Nature Chemical Biology · doi:10.1038/nchembio.283 · Cited by 552 · see citing works
Self-citationSelf-Assembly of Aβ <sub>1</sub> <sub>-</sub> <sub>42</sub> into Globular Neurotoxins
Chromy, B. A., Nowak, R. J., Lambert, M. P., Viola, K. L., Chang, L., Velasco, P. T., Jones, B. W., Fernandez, S. J., Lacor, P. N., Horowitz, P., et al. (2003) · Biochemistry · doi:10.1021/bi030029q · Cited by 522 · see citing works
Chen, S. W., Drakulić, S., Deas, E., Ouberai, M. M., Aprile, F. A., Arranz, R., Ness, S., Roodveldt, C., Guilliams, T., Genst, E. D., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1421204112 · Cited by 471 · see citing works
Self-citationDeas, E., Cremades, N., Angelova, P. R., Ludtmann, M. H. R., Yao, Z., Chen, S. W., Horrocks, M. H., Banushi, B., Little, D., Devine, M. J., et al. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6343 · Cited by 360 · see citing works
Self-citationLipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice
Martins, I. C., Kuperstein, I., Wilkinson, H. R., Maes, E., Vanbrabant, M., Jonckheere, W., Gelder, P. V., Hartmann, D., D’Hooge, R., Strooper, B. D., et al. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601953 · Cited by 311 · see citing works
Amyloid‐beta oligomerization in Alzheimer dementia versus high‐pathology controls
Esparza, T. J., Zhao, H., Cirrito, J. R., Cairns, N. J., Bateman, R. J., Holtzman, D. M., & Brody, D. L. (2012) · Annals of Neurology · doi:10.1002/ana.23748 · Cited by 304 · see citing works
Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins
Ciryam, P., Tartaglia, G. G., Morimoto, R. I., Dobson, C. M., & Vendruscolo, M. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.09.043 · Cited by 270 · see citing works
Self-citationPathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity
Choi, M. L., Chappard, A., Singh, B., Maclachlan, C., Rodrigues, M., Fedotova, E. I., Berezhnov, A. V., De, S., Peddie, C. J., Athauda, D. S., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01140-3 · Cited by 257 · see citing works
The release of toxic oligomers from α-synuclein fibrils induces dysfunction in neuronal cells
Cascella, R., Chen, S. W., Bigi, A., Camino, J. D., Xu, C. K., Dobson, C. M., Chiti, F., Cremades, N., & Cecchi, C. (2021) · Nature Communications · doi:10.1038/s41467-021-21937-3 · Cited by 236 · see citing works
Self-citationPaleologou, K. E., Kragh, C. L., Mann, D. M. A., Salem, S. A., Al‐Shami, R., Allsop, D., Hassan, A. H. M., Jensen, P. H., & El‐Agnaf, O. M. A. (2008) · Brain · doi:10.1093/brain/awn349 · Cited by 225 · see citing works
Conformational Differences between Two Amyloid β Oligomers of Similar Size and Dissimilar Toxicity
Ladiwala, A. R. A., Litt, J., Kane, R. S., Aucoin, D., Smith, S. O., Ranjan, S., Davis, J., Nostrand, W. E. V., & Tessier, P. M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.329763 · Cited by 223 · see citing works
Self-citationHabchi, J., Chia, S., Limbocker, R., Mannini, B., Ahn, M., Perni, M., Hansson, O., Arosio, P., Kumita, J. R., Challa, P. K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1615613114 · Cited by 220 · see citing works
Self-citationKinetic model of the aggregation of alpha-synuclein provides insights into prion-like spreading
Iljina, M., Garcia, G. A., Horrocks, M. H., Tosatto, L., Choi, M. L., Ganzinger, K. A., Abramov, A. Y., Gandhi, S., Wood, N. W., Cremades, N., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1524128113 · Cited by 219 · see citing works
Self-citationCa2+ is a key factor in α-synuclein-induced neurotoxicity
Angelova, P. R., Ludtmann, M. H. R., Horrocks, M. H., Negoda, A. E., Cremades, N., Klenerman, D., Dobson, C. M., Wood, N. W., Pavlov, E. V., Gandhi, S., et al. (2016) · Journal of Cell Science · doi:10.1242/jcs.180737 · Cited by 193 · see citing works
Self-citationKinetic diversity of amyloid oligomers
Dear, A. J., Michaels, T. C. T., Meisl, G., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1922267117 · Cited by 187 · see citing works
Miller, E. C., Teravskis, P. J., Dummer, B. W., Zhao, X., Huganir, R. L., & Liao, D. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12507 · Cited by 131 · see citing works
Evangelisti, E., Cascella, R., Becatti, M., Marrazza, G., Dobson, C. M., Chiti, F., Stefani, M., & Cecchi, C. (2016) · Scientific Reports · doi:10.1038/srep32721 · Cited by 131 · see citing works
Self-citationConserved features of intermediates in amyloid assembly determine their benign or toxic states
Krishnan, R., Goodman, J. L., Mukhopadhyay, S., Pacheco, C. D., Lemke, E. A., Deniz, A. A., & Lindquist, S. L. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209527109 · Cited by 130 · see citing works
Defining α-synuclein species responsible for Parkinson’s disease phenotypes in mice
Froula, J. M., Castellana-Cruz, M., Anabtawi, N. M., Camino, J. D., Chen, S. W., Thrasher, D. R., Freire, J., Yazdi, A. A., Fleming, S., Dobson, C. M., et al. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.007743 · Cited by 129 · see citing works
Self-citationIdentification of on- and off-pathway oligomers in amyloid fibril formation
Dear, A. J., Meisl, G., Šarić, A., Michaels, T. C. T., Kjærgaard, M., Linse, S. S., & Knowles, T. P. J. (2020) · Chemical Science · doi:10.1039/c9sc06501f · Cited by 124 · see citing works
Structural Characteristics of α-Synuclein Oligomers
Cremades, N., Chen, S. W., & Dobson, C. M. (2016) · International review of cytology · doi:10.1016/bs.ircmb.2016.08.010 · Cited by 118 · see citing works
Self-citationFani, G., Mannini, B., Vecchi, G., Cascella, R., Cecchi, C., Dobson, C. M., Vendruscolo, M., & Chiti, F. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00811 · Cited by 102 · see citing works
Self-citationMembrane Interactions and Toxicity by Misfolded Protein Oligomers
Gonzalez-Garcia, M., Fusco, G., & Simone, A. D. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.642623 · Cited by 73 · see citing works
Zampagni, M., Cascella, R., Casamenti, F., Grossi, C., Evangelisti, E., Wright, D., Becatti, M., Liguri, G., Mannini, B., Campioni, S., et al. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01239.x · Cited by 70 · see citing works
Self-citationRosano, C., Zuccotti, S., Bucciantini, M., et al. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)00713-1 · Cited by 70 · see citing works
Mukhopadhyay, S., Nayak, P. K., Udgaonkar, J. B., et al. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.02.006 · Cited by 66 · see citing works
Limbocker, R., Mannini, B., Ruggeri, F. S., Cascella, R., Xu, C. K., Perni, M., Chia, S., Chen, S. W., Habchi, J., Bigi, A., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-01140-8 · Cited by 63 · see citing works
Self-citationChaperones as Suppressors of Protein Misfolded Oligomer Toxicity
Mannini, B., & Chiti, F. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00098 · Cited by 60 · see citing works
Self-citationSoluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload
Cascella, R., Evangelisti, E., Bigi, A., Becatti, M., Fiorillo, C., Stefani, M., Chiti, F., & Cecchi, C. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170340 · Cited by 56 · see citing works
Self-citationCamino, J. D., Gracia, P., Chen, S. W., et al. (2020) · Chemical Science · doi:10.1039/d0sc05297c · Cited by 52 · see citing works
The Toxicity of Misfolded Protein Oligomers Is Independent of Their Secondary Structure
Vivoli, M., Cascella, R., Chen, S. W., Fusco, G., Simone, A. D., Dobson, C. M., Cecchi, C., & Chiti, F. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00324 · Cited by 51 · see citing works
Self-citationLimbocker, R., Errico, S., Barbut, D., Knowles, T. P. J., Vendruscolo, M., Chiti, F., & ZASLOFF, M. A. (2021) · Natural Product Reports · doi:10.1039/d1np00042j · Cited by 51 · see citing works
Self-citationProbing the Origin of the Toxicity of Oligomeric Aggregates of α-Synuclein with Antibodies
Cascella, R., Perni, M., Chen, S. W., Fusco, G., Cecchi, C., Vendruscolo, M., Chiti, F., Dobson, C. M., & Simone, A. D. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00312 · Cited by 50 · see citing works
Self-citationFani, G., Torre, C. E. L., Cascella, R., Cecchi, C., Vendruscolo, M., & Chiti, F. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04513-w · Cited by 43 · see citing works
Self-citationAmyloid-β oligomer synaptotoxicity is mimicked by oligomers of the model protein HypF-N
Tatini, F., Pugliese, A. M., Traini, C., Niccoli, S., Maraula, G., Dami, T. E., Mannini, B., Scartabelli, T., Pedata, F., Casamenti, F., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.03.020 · Cited by 32 · see citing works
Self-citationStructural differences between toxic and nontoxic HypF-N oligomers
Capitini, C., Patel, J. R., Natalello, A., et al. (2018) · Chemical Communications · doi:10.1039/c8cc03446j · Cited by 29 · see citing works
Bigi, A., Ermini, E., Chen, S. W., Cascella, R., & Cecchi, C. (2021) · Life · doi:10.3390/life11050431 · Cited by 28 · see citing works
Self-citationTargeting Pathological Amyloid Aggregates with Conformation-Sensitive Antibodies
Bigi, A., Loffredo, G., Cascella, R., & Cecchi, C. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666201109093848 · Cited by 27 · see citing works
Self-citationCalamai, M., Evangelisti, E., Cascella, R., Parenti, N., Cecchi, C., Stefani, M., & Pavone, F. S. (2015) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2015.12.009 · Cited by 25 · see citing works
Self-citationOropesa‐Nuñez, R., Seghezza, S., Dante, S., Diaspro, A., Cascella, R., Cecchi, C., Stefani, M., Chiti, F., & Canale, C. (2016) · Oncotarget · doi:10.18632/oncotarget.10449 · Cited by 25 · see citing works
Self-citationKinetic profiling of therapeutic strategies for inhibiting the formation of amyloid oligomers
Michaels, T. C. T., Dear, A. J., Cohen, S. I. A., Vendruscolo, M., & Knowles, T. P. J. (2022) · The Journal of Chemical Physics · doi:10.1063/5.0077609 · Cited by 24 · see citing works
Self-citationThe yeast prion [PSI+]: Molecular insights and functional consequences
Serio, T. R., & Lindquist, S. L. (2001) · Advances in protein chemistry · doi:10.1016/s0065-3233(01)59012-9 · Cited by 19 · see citing works
Errico, S., Ramshini, H., Capitini, C., Canale, C., Spaziano, M., Barbut, D., Calamai, M., Zasloff, M., Oropesa-Nuñez, R., Vendruscolo, M., et al. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00327 · Cited by 19 · see citing works
Self-citationHow epigallocatechin gallate binds and assembles oligomeric forms of human alpha-synuclein
Andersen, C. B., Yoshimura, Y., Nielsen, J., et al. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100788 · Cited by 18 · see citing works
Perni, M., Mannini, B., Xu, C. K., Kumita, J. R., Dobson, C. M., Chiti, F., & Vendruscolo, M. (2021) · Scientific Reports · doi:10.1038/s41598-021-93527-8 · Cited by 14 · see citing works
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Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies
Buccellato, F. R., D’Anca, M., Tartaglia, G. M., Del Fabbro, M., Scarpini, E., & Galimberti, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241813900 · Cited by 94 · see citing works
“Each proteinopathy is characterized by different fibrillar aggregates, such as amyloid-β (A β ) plaques and neurofibrillary tangles of tau in AD, Lewy bodies of α - α -synuclein ( α Syn) in PD, or amyloid deposits of an immunoglobulin light chain in AL [16].”
Background
- Authors
- Limbocker, R., Cremades, N., Cascella, R., Tessier, P. M., Vendruscolo, M., & Chiti, F.
- Affiliations
- United States Military Academy (US)
- Universidad de Zaragoza (ES)
- University of Florence (IT)
- University of Michigan (US)
- University of Cambridge (GB)
- Corresponding author
- Chiti, Fabrizio
- ORCID
- Venue
- Accounts of Chemical Research
- Publisher
- American Chemical Society (ACS)
- Published
- 2023-04-18
- Volume
- 56
- Issue
- 12
- Pages
- 1395-1405
- ISSN
- 0001-4842 (ISSN-L)
- 1520-4898
- PMC
- PMC10286310
- OpenAlex
- W4366251352
- Cited by
- 48
- References
- 54
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 14 · 2023: 4
- FWCI
- 8.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Accounts of Chemical Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion, other-oa)
- Zaguan (University of Zaragoza Repository) (submittedVersion, cc-by)
- Funders
- European Union Agency for Network and Information Security
- Regione Toscana
- Defense Threat Reduction Agency
- Division of Chemical, Bioengineering, Environmental, and Transport Systems (1605266, 1813963)
- Army Research Laboratory
- National Institutes of Health (R35GM136300, RF1AG059723)
- Ministerio de Ciencia e Innovaci?n (MCIN/AEI/10.13039/501100011033, PGC2018-096335-B100)
- Airalzh Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- oligomer toxicity, amyloid-beta, alpha-synuclein, synucleinopathies, Alzheimer's disease, Parkinson's disease, amyloid fibril formation, neurodegenerative diseases
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Escherichia coli, Amyloid beta-Peptides, Proteostasis Deficiencies
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