Aggregation and neurotoxicity of α-synuclein and related peptides

EI-Agnaf, O. M. A.; Irvine, G. B.

doi:10.1042/bst0300559

Cited by 152Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Aggregation and neurotoxicity of α-synuclein and related peptides

EI-Agnaf, O. M. A., Irvine, G. B.·2002·Biochemical Society Transactions

DOI 10.1042/bst0300559

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Abstract

Fibrillar deposits of alpha-synuclein occur in several neurodegenerative diseases. Two mutant forms of alpha-synuclein have been associated with early-onset Parkinson's disease, and a fragment has been identified as the non-amyloid-beta peptide component of Alzheimer's disease amyloid (NAC). Upon aging, solutions of alpha-synuclein and NAC change conformation to beta-sheet, detectable by CD spectroscopy, and form oligomers that deposit as amyloid-like fibrils, detectable by electron microscopy. These aged peptides are also neurotoxic. Experiments on fragments of NAC have enabled the region of NAC responsible for its aggregation and toxicity to be identified. NAC(8-18) is the smallest fragment that aggregates, as indicated by the concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. Fragments NAC(8-18) and NAC(8-16) are toxic, whereas NAC(12-18), NAC(9-16) and NAC(8-15) are not. Hence residues 8-16 of NAC comprise the region crucial for toxicity. Toxicity induced by alpha-synuclein, NAC and NAC(1-18) oligomers occurs via an apoptotic mechanism, possibly initiated by oxidative damage, since these peptides liberate hydroxyl radicals in the presence of iron. Molecules with anti-aggregational and/or antioxidant properties may therefore be potential therapeutic agents.

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Ferric iron can, in vitro, catalyse the conversion of α-synuclein from the α-helix to the β-sheet conformation that is present in Lewy bodies.
“Ferric iron can, in vitro, catalyse the conversion of α-synuclein from the α-helix to the β-sheet conformation that is present in Lewy bodies.113,114”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [113]

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Transient β -hairpin formation in α -synuclein monomer revealed by coarse-grained molecular dynamics simulation
Yu, H., Han, W., Ma, W., & Schulten, K. J. (2015) · The Journal of Chemical Physics · doi:10.1063/1.4936910 · Cited by 99 · see citing works
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Lendel, C., Bertoncini, C. W., Cremades, N., Waudby, C. A., Vendruscolo, M., Dobson, C. M., Schenk, D., Christodoulou, J. C., & Tóth, G. (2009) · Biochemistry · doi:10.1021/bi901285x · Cited by 97 · see citing works
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“It is responsible for protein-protein interactions and confers on α-syn the ability to undergo a conformational change from a random coil to an aggregation-prone β-sheet structure [58] leading to the formation of amyloid-like fibrils [59].”
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Zhu, M., Han, S., Zhou, F., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400004200 · Cited by 91 · see citing works
Neuroprotection by iron chelator against proteasome inhibitor-induced nigral degeneration
Zhang, X., Xie, W., Qu, S., Pan, T., Wang, X., & Le, W. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.05.150 · Cited by 87 · see citing works
Selectivity of the ubiquitin pathway for oxidatively modified proteins: relevance to protein precipitation diseases
Dudek, E. J., Shang, F., Liu, Q. L., Valverde, P., Hobbs, M., & Taylor, A. (2005) · The FASEB Journal · doi:10.1096/fj.05-4049fje · Cited by 86 · see citing works
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Chen, Q., Thorpe, J., & Keller, J. N. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501308200 · Cited by 83 · see citing works
Amyloidogenic sequences in native protein structures
Tzotzos, S. J., & Doig, A. J. (2009) · Protein Science · doi:10.1002/pro.314 · Cited by 83 · see citing works
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Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro
Köppen, J., Schulze, A., Machner, L., Wermann, M., Eichentopf, R., Guthardt, M., Hähnel, A., Klehm, J., Kriegeskorte, M.-C., Hartlage‐Rübsamen, M., et al. (2020) · Molecules · doi:10.3390/molecules25030580 · Cited by 78 · see citing works
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Guo, J., Yue, F., Song, D., Bousset, L., Liang, X., Tang, J., Yuan, L., Li, W., Melki, R., Tang, Y. C., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-020-03369-x · Cited by 74 · see citing works
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Tompa, P. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07250.x · Cited by 72 · see citing works
Glycosaminoglycans have variable effects on α-synuclein aggregation and differentially affect the activities of the resulting amyloid fibrils
Mehra, S., Ghosh, D., Kumar, R., Mondal, M., Gadhe, L. G., Das, S., Arunagiri, A., Jha, N. N., Jacob, R. S., Chatterjee, D., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.004267 · Cited by 74 · see citing works
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Developmental exposure to pesticides zineb and/or endosulfan renders the nigrostriatal dopamine system more susceptible to these environmental chemicals later in life
Jia, Z., & Misra, H. P. (2007) · NeuroToxicology · doi:10.1016/j.neuro.2007.04.003 · Cited by 68 · see citing works
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Lv, G., Kumar, A., Giller, K., Orcellet, M. L., Riedel, D., Fernández, C. O., Becker, S., & Lange, A. (2012) · Journal of Molecular Biology · doi:10.1016/j.jmb.2012.04.009 · Cited by 67 · see citing works
Protein Aggregation in Retinal Cells and Approaches to Cell Protection
Surgucheva, I. G., Ninkina, N. N., Buchman, V. L., Grasing, K., & Surguchov, A. P. (2005) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-005-8474-1 · Cited by 64 · see citing works
“The absence of protective effect by α-synuclein that we observed in our experiments may be explained by its ability to aggregate and inhibit proteasomal activity (El-Agnaf and Irvine, 2002; Snyder et al., 2003, 2005).”
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Arachidonic acid mediates the formation of abundant alpha-helical multimers of alpha-synuclein
Iljina, M., Tosatto, L., Choi, M. L., Sang, J. C., Ye, Y., Hughes, C. D., Bryant, C. E., Gandhi, S., & Klenerman, D. (2016) · Scientific Reports · doi:10.1038/srep33928 · Cited by 62 · see citing works
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Ageing neuroinflammation and neurodegeneration
Ward, R. J. (2015) · Frontiers in Bioscience-Scholar · doi:10.2741/s433 · Cited by 63 · see citing works
Calcium dyshomeostasis and neurotoxicity of Alzheimer’s β-amyloid protein
Kawahara, M., Kato‐Negishi, M., & Sadakane, Y. (2009) · Expert Review of Neurotherapeutics · doi:10.1586/ern.09.28 · Cited by 55 · see citing works
Animal models of pheochromocytoma.
Tischler, A. S., Powers, J. F., & Alroy, J. (2004) · PubMed · doi:10.14670/hh-19.883 · Cited by 55 · see citing works
Role of α-synuclein aggregation and the nuclear factor E2-related factor 2/heme oxygenase-1 pathway in iron-induced neurotoxicity
He, Q. W., Song, N., Jia, F., Xu, H., Yu, X., Xie, J., & Jiang, H. F. (2013) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.02.012 · Cited by 52 · see citing works
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Gasser, T. (2012) · CRC Press eBooks · doi:10.1201/b12948-15 · Cited by 50 · see citing works
Exploring pathological link between antimicrobial and amyloid peptides
Tang, Y., Zhang, Y., Zhang, D., Liu, Y., Nussinov, R., & Zheng, J. (2024) · Chemical Society Reviews · doi:10.1039/d3cs00878a · Cited by 50 · see citing works
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Chavarría, C., Ivagnes, R., & Souza, J. M. (2022) · Biomolecules · doi:10.3390/biom12050655 · Cited by 47 · see citing works
Genetic factors involved in the pathogenesis of Parkinson's disease
Lee, F. J. S., & Liu, F. (2008) · Brain Research Reviews · doi:10.1016/j.brainresrev.2008.02.001 · Cited by 43 · see citing works
Irreversible formation of intermediate BSA oligomers requires and induces conformational changes
Vaiana, S. M., Emanuele, A., Palma‐Vittorelli, M. B., et al. (2004) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.20074 · Cited by 45 · see citing works
Parkinsons Disease: Genetics and Beyond
Inamdar, N., Arulmozhi, D. K., Tandon, A., & Bodhankar, S. L. (2007) · Current Neuropharmacology · doi:10.2174/157015907780866893 · Cited by 44 · see citing works
“The amino terminus can bind to lipids and play role in association with lipid micelles, synaptic vesicles, lipid bilayer [63, 131] ii) The central portion of SN known as non A component of plaque (NACP) has residues 61-95 and is responsible for various confirmations of SN [266] NACP helps to attain random coil, sheet…”
Background
Distinct phases of free α‐synuclein—A Monte Carlo study
Jónsson, S. Æ., Mohanty, S., & Irbäck, A. (2012) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.24107 · Cited by 43 · see citing works
α-Synuclein: A potent inducer of tau pathology
Geddes, J. W. (2005) · Experimental Neurology · doi:10.1016/j.expneurol.2004.12.002 · Cited by 43 · see citing works
The role of ferroptosis in neurodegenerative diseases
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Horváth, M., Kovács, G. G., Kövari, V., Majtényi, K., Hurd, Y. L., & Keller, É. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2398-07.2007 · Cited by 42 · see citing works
Peptide ligand screening of α-synuclein aggregation modulators by in silico panning
Abe, K., Kobayashi, N., Sode, K., & Ikebukuro, K. (2007) · BMC Bioinformatics · doi:10.1186/1471-2105-8-451 · Cited by 41 · see citing works
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Ricco, R. D., Valensin, D., Dell’Acqua, S., Casella, L., Dorlet, P., Faller, P., & Hureau, C. (2015) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.5b00120 · Cited by 40 · see citing works
A Proposed Atomic Structure of the Self-Assembly of the Non-Amyloid-β Component of Human α-Synuclein As Derived by Computational Tools
Atsmon‐Raz, Y., & Miller, Y. (2015) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.5b03760 · Cited by 37 · see citing works
Cerebrospinal Fluid Biomarkers for Dementia with Lewy Bodies
Mukaetova‐Ladinska, E. B., Monteith, R., & Perry, E. K. (2010) · International Journal of Alzheimer s Disease · doi:10.4061/2010/536538 · Cited by 37 · see citing works
Conserved core of amyloid fibrils of wild type and A30P mutant α‐synuclein
Cho, M., Kim, H., Fernández, C. O., Becker, S., & Zweckstetter, M. (2010) · Protein Science · doi:10.1002/pro.570 · Cited by 37 · see citing works
GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice
Cressatti, M., Song, W., Turk, A. Z., Garabed, L. R., Benchaya, J. A., Galindez, C., Liberman, A., & Schipper, H. M. (2019) · Glia · doi:10.1002/glia.23645 · Cited by 35 · see citing works
Parkinson's disease as a member of Prion-like disorders
Herva, M. E., & Spillantini, M. G. (2014) · Virus Research · doi:10.1016/j.virusres.2014.10.016 · Cited by 31 · see citing works
Effect of α-Synuclein on Amyloid β-Induced Toxicity: Relevance to Lewy Body Variant of Alzheimer Disease
Resende, R., Marques, S., Ferreiro, E. B., Simões, I., Oliveira, C. R., & Pereira, C. (2013) · Neurochemical Research · doi:10.1007/s11064-013-0982-7 · Cited by 31 · see citing works
Tilted properties of the 67–78 fragment of α‐synuclein are responsible for membrane destabilization and neurotoxicity
Crowet, J., Lins, L., Dupiereux-Fettweis, I., Elmoualija, B., Lorin, A., Charloteaux, B., Stroobant, V., Heinen, E., & Brasseur, R. (2007) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.21483 · Cited by 30 · see citing works
DOPAL is transmissible to and oligomerizes alpha-synuclein in human glial cells
Jinsmaa, Y., Sullivan, P., Sharabi, Y., & Goldstein, D. S. (2015) · Autonomic Neuroscience · doi:10.1016/j.autneu.2015.12.008 · Cited by 29 · see citing works
Conformational Plasticity in α-Synuclein and How Crowded Environment Modulates It
Menon, S., & Mondal, J. (2023) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.3c00982 · Cited by 28 · see citing works
Macroautophagy and the proteasome are differently involved in the degradation of alpha-synuclein wild type and mutated A30P in an in vitro inducible model (PC12/TetOn)
Batelli, S., Peverelli, E., Rodilossi, S., Forloni, G., & Albani, D. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.08.030 · Cited by 27 · see citing works
Interaction of baicalein and copper with α-synuclein: Electrochemical approach to Parkinson’s Disease
Chan, T., Chow, A. M., Tang, D. W. F., et al. (2010) · Journal of Electroanalytical Chemistry · doi:10.1016/j.jelechem.2010.07.015 · Cited by 26 · see citing works
Navigating the dynamic landscape of alpha-synuclein morphology: a review of the physiologically relevant tetrameric conformation
Lucas, H. R., & Fernández, R. D. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.265792 · Cited by 26 · see citing works
“The NACore, also referred to as NAC(8–18) (el-Agnaf and Irvine, 2002), was observed to serve as an initiator of toxic oligomerization; however, the tetrameric helical species buried this region, supporting the concept of the helical tetramer as a nontoxic multimer.”
Effect of N-methyl-D-aspartate (NMDA) receptor antagonists on α-synuclein-evoked neuronal nitric oxide synthase activation in the rat brain
Adamczyk, A., Czapski, G. A., Wilkaniec, A., & Strosznajder, J. B. (2009) · Pharmacological Reports · doi:10.1016/s1734-1140(09)70170-7 · Cited by 22 · see citing works
Reciprocal Induction Between α-Synuclein and β-Amyloid in Adult Rat Neurons
Majd, S., Chegini, F., Chataway, T., Zhou, X., & Gai, W. (2012) · Neurotoxicity Research · doi:10.1007/s12640-012-9330-y · Cited by 22 · see citing works
“The toxicity effects of oligomeric and fibrillar forms of Ab and a-Syn have been shown in previous reports (Copani et al. 1999; El-Agnaf and Irvine 2002; Heinitz et al. 2006; Okada et al. 2007).”
Result
Ferroptosis and cognitive impairment: Unraveling the link and potential therapeutic targets
Naderi, S., Khodagholi, F., Janahmadi, M., Motamedi, F., Torabi, A., Batool, Z., Heydarabadi, M. F., & Pourbadie, H. G. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110210 · Cited by 22 · see citing works
Overexpression of α‐synuclein decreased viability and enhanced sensitivity to prostaglandin E2, hydrogen peroxide, and a nitric oxide donor in differentiated neuroblastoma cells
Prasad, J. E., Kumar, B., Andreatta, C. P., et al. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20058 · Cited by 21 · see citing works
Complexation of NAC-Derived Peptide Ligands with the C-Terminus of α-Synuclein Accelerates Its Aggregation
Jha, N. N., Ranganathan, S., Kumar, R., Mehra, S., Panigrahi, R., Navalkar, A., Ghosh, D., Kumar, A., Padinhateeri, R., & Maji, S. K. (2017) · Biochemistry · doi:10.1021/acs.biochem.7b01090 · Cited by 19 · see citing works
Natural flavonoids from herbs and nutraceuticals as ferroptosis inhibitors in central nervous system diseases: current preclinical evidence and future perspectives
Li, Q., Yang, X., & Li, T. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1570069 · Cited by 22 · see citing works
The role of α-synuclein in neurodegeneration — An update
Jellinger, K. A. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0013-1 · Cited by 19 · see citing works
Interaction-based evaluation of the propensity for amyloid formation with cross-β structure
Saiki, M., Konakahara, T., & Morii, H. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.03.089 · Cited by 19 · see citing works
Salient Features of Monomeric Alpha-Synuclein Revealed by NMR Spectroscopy
Kim, D.-H., Lee, J., Mok, K. H., Lee, J., & Han, K. (2020) · Biomolecules · doi:10.3390/biom10030428 · Cited by 18 · see citing works
“The primary structure of αS can be separated into three parts: (i) the N-terminal region (residues 1–60) has a series of 11-amino acid repeats with a conserved KTKEGV motif that, upon binding to synthetic lipid vesicles or detergent micelles in vitro, adopts a highly helical conformation [26–28]; (ii) the residues 61–…”
Background
Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity
Gupta, V. R., Salim, S., Hmila, I., Vaikath, N. N., Sudhakaran, I. P., Ghanem, S. S., Majbour, N. K., Abdulla, S. A., Emara, M. M., Abdesselem, H., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-65035-8 · Cited by 18 · see citing works
Early oligomerization stages for the non-amyloid component of α-synuclein amyloid
Eugene, C., Laghaei, R., & Mousseau, N. (2014) · The Journal of Chemical Physics · doi:10.1063/1.4896381 · Cited by 16 · see citing works
Targeting of Disordered Proteins by Small Molecules in Neurodegenerative Diseases
Longhena, F., Spano, P., & Bellucci, A. (2017) · Handbook of experimental pharmacology · doi:10.1007/164_2017_60 · Cited by 17 · see citing works
The potential of natural products to inhibit abnormal aggregation of α-Synuclein in the treatment of Parkinson’s disease
Yang, K., Lv, Z., Wen, Z., Lai, G., Zheng, C., Qi, F., Zhao, C., Hu, K., Chen, X., Fu, F., et al. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1468850 · Cited by 18 · see citing works
The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin
Skaanning, L. K., Santoro, A., Skamris, T., Martinsen, J. H., D’Ursi, A. M., Bucciarelli, S., Vestergaard, B., Bugge, K., Langkilde, A. E., & Kragelund, B. B. (2020) · Biomolecules · doi:10.3390/biom10081192 · Cited by 14 · see citing works
“When the central NAC region was fully missing or if the fragments only carried parts of the NAC region, fibrillation and/or aggregation was/were limited or not observed (1–60 [69,70], 71–140 [76], 61–78 [77], 68–76 [77], 68–78 [77] and 69–79 [77]).”

Authors: EI-Agnaf, O. M. A., & Irvine, G. B.
Affiliations: Lancaster University (GB)
Queen's University Belfast (GB)
Venue: Biochemical Society Transactions
Publisher: Portland Press Ltd.
Published: 2002-08-01
Volume: 30
Issue: 4
Pages: 559-565
ISSN: 0300-5127 (ISSN-L)
1470-8752
DOI: 10.1042/bst0300559
OpenAlex: W2020351832
Cited by: 151
References: 0
Citations by year: 2026: 3 · 2025: 2 · 2024: 7 · 2023: 4 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 3 · 2018: 6 · 2017: 4 · 2016: 3 · 2015: 11 · 2014: 7 · 2013: 5 · 2012: 8
FWCI: 5.57
Type: journal article
Language: en
Open access: closed
Locations: Biochemical Society Transactions (publishedVersion)
PubMed (publishedVersion)
Research Portal (Queen's University Belfast) (submittedVersion)
Topics: Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: alpha-synuclein, neurotoxicity, peptide aggregation, amyloid fibrils, Parkinson's disease, β-sheet conformation, oligomers, oxidative damage, hydroxyl radicals, iron, antioxidant therapy, peptide fragments
MeSH terms: Alzheimer Disease, Animals, Brain, Cell Survival, Humans, Molecular Weight, Nerve Tissue Proteins, Neurotoxins, Phosphoproteins, Protein Conformation, PC12 Cells, Protein Structure, Secondary, Rats, Synucleins, alpha-Synuclein

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Aggregation and neurotoxicity of α-synuclein and related peptides

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