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Initiation and Synergistic Fibrillization of Tau and Alpha-Synuclein
Abstract
Alpha-synuclein (alpha-syn) and tau polymerize into amyloid fibrils and form intraneuronal filamentous inclusions characteristic of neurodegenerative diseases. We demonstrate that alpha-syn induces fibrillization of tau and that coincubation of tau and alpha-syn synergistically promotes fibrillization of both proteins. The in vivo relevance of these findings is grounded in the co-occurrence of alpha-syn and tau filamentous amyloid inclusions in humans, in single transgenic mice that express A53T human alpha-syn in neurons, and in oligodendrocytes of bigenic mice that express wild-type human alpha-syn plus P301L mutant tau. This suggests that interactions between alpha-syn and tau can promote their fibrillization and drive the formation of pathological inclusions in human neurodegenerative diseases.
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“Evidence suggests that Aβ can directly affect α-synuclein toxicity, and it is also known that tau protein and α-synuclein can directly interact promoting their co-assembly [124–126].”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [125]
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“Emerging evidence indicates that tau and α-synuclein might overlap in the pathological features of inclusion body diseases and possibly interact with and affect one another (Lee et al. 2004b; Galpern and Lang 2006 ).”
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“fibrillization in heterologous proteins which are prone to form amyloid, in what has been called abnormal conformational mimicry [7;8].”
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“Furthermore, α-Syn has been shown to initiate tau fibrillization and aggregation (Geddes 2005; Giasson et al. 2003; Riedel et al. 2009; Waxman and Giasson 2011). α-Syn is a highly soluble, natively unfolded protein with the capability to self-aggregate in a nucleation-dependent process.”
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“α-Syn Tau 1 co-aggregation seeding, colocalization, affinity chromatography, FRET [25,28,41,50,69,110,118]”
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“Second, it was previously shown that αsynuclein and tau can synergistically promote their mutual aggregation, suggesting that synergistic interactions between the two pathological proteins might exacerbate ADRD pathology (Giasson et al., 2003; Oikawa et al., 2016).”
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“Despite the physiological and pathological discrepancies between α-Syn and tau, many investigations increasingly demonstrate that Lewy bodies are composed of both α-Syn and fibrillar tau; further, a hypothesis has been postulated that α-Syn can trigger tau fibrillization, and concomitant with tau, direct interaction w…”
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Single particle detection and characterization of synuclein co-aggregation
Giese, A., Bader, B., Bieschke, J., Schaffar, G., Odoy, S., Kahle, P. J., Haass, C., & Kretzschmar, H. A. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.06.025 · Cited by 47
Interaction of α‐synuclein and tau genotypes in Parkinson's disease
Mamah, C., Lesnick, T. G., Lincoln, S., Strain, K. J., de Andrade, M., Bower, J. H., Ahlskog, J. E., Rocca, W. A., Farrer, M. J., & Maraganore, D. M. (2005) · Annals of Neurology · doi:10.1002/ana.20387 · Cited by 47
Synucleins: Are they two‐edged swords?
Surguchov, A. P. (2012) · Journal of Neuroscience Research · doi:10.1002/jnr.23149 · Cited by 46
EF hd2 is a novel amyloid protein associated with pathological tau in Alzheimer's disease
Ferrer‐Acosta, Y., Rodríguez‐Cruz, E. N., Orange, F., Jesús‐Cortés, H. D., Madera, B., Vaquer‐Alicea, J., Ballester, J., Guinel, M. J. ‐., Bloom, G. S., & Vega, I. E. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12155 · Cited by 47
Li, Y., Zhu, Z., Chen, J., Zhang, M., Yang, Y., & Huang, P. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00161 · Cited by 47
Alpha-Synuclein and Cognitive Decline in Parkinson Disease
Fan, T.-S., Liu, S. C.-H., & Wu, R. (2021) · Life · doi:10.3390/life11111239 · Cited by 47
Walker, L., & Attems, J. (2023) · Journal of Parkinson s Disease · doi:10.3233/jpd-230154 · Cited by 48
Phosphorylation of serine 305 in tau inhibits aggregation
Strang, K. H., Sorrentino, Z. A., Riffe, C. J., Gorion, K.-M. M., Vijayaraghavan, N., Golde, T. E., & Giasson, B. I. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.11.011 · Cited by 46
Self-citationPrionoid Proteins in the Pathogenesis of Neurodegenerative Diseases
Wells, C., Brennan, S. E., Keon, M., & Saksena, N. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00271 · Cited by 46
“There is evidence of a synergistic interaction between the Tau protein and α-synuclein, as co-occurrence leads to accelerated fibrillization of both proteins (Giasson et al., 2003).”
BackgroundDefining and predicting transdiagnostic categories of neurodegenerative disease
Cornblath, E. J., Robinson, J. L., Irwin, D. J., Lee, E. B., Lee, V. M. ‐., Trojanowski, J. Q., & Bassett, D. S. (2020) · Nature Biomedical Engineering · doi:10.1038/s41551-020-0593-y · Cited by 48
“[23] Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, et al.”
BackgroundSelf-citationAssessing the causes and consequences of co-polymerization in amyloid formation
Sarell, C. J., Stockley, P. G., & Radford, S. E. (2013) · Prion · doi:10.4161/pri.26415 · Cited by 44
“Further in vitro studies have shown that co-incubation of tau and α-synuclein induces polymerization of both proteins and this effect was observed for all six tau isoforms (Row 9, Table 1).(33) Immunogold labeling revealed that the individual fibrils are mostly homopolymers, but some fibrils were labeled for both α-sy…”
BackgroundInfluentialXia, Y., Sorrentino, Z. A., Kim, J. D., Strang, K. H., Riffe, C. J., & Giasson, B. I. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010178 · Cited by 48
Self-citationGenetic Mouse Models of Neurodegenerative Diseases
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“It is also possible that aggregates of NF-L and mutant SOD1 protein have mutually synergistic effects (60) and that aggregates of mutant SOD1 may also enhance the aggregation of NF-L protein and p190RhoGEF and loss of NF-L expression.”
BackgroundInduction of AApoAII amyloidosis by various heterogeneous amyloid fibrils
Fu, X., Korenaga, T., Fu, L., Xing, Y., Guo, Z., Matsushita, T., Hosokawa, M., Naiki, H., Baba, S., Kawata, Y., et al. (2004) · FEBS Letters · doi:10.1016/s0014-5793(04)00295-9 · Cited by 44
Neuroimmune Tau Mechanisms: Their Role in the Progression of Neuronal Degeneration
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Carnwath, T., Mohammed, R., & Tsiang, D. (2018) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s166322 · Cited by 43
“25 These contradictory results may be due to the different promoters that α -synuclein was expressed under, the cells of the brain analyzed (oligodendricytes vs neurons of the striatum) or the method of staining (thioflavin-S vs tau).”
Christensen, L. F. B., Jensen, K. F., Nielsen, J., Vad, B. S., Christiansen, G., & Otzen, D. E. (2019) · ACS Omega · doi:10.1021/acsomega.8b03590 · Cited by 45
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“(4) In reciprocation, tau can promote α-synuclein’s phosphorylation by GSK3β and α-synuclein aggregation (Giasson et al., 2003; Credle et al., 2015).”
BackgroundInfluentialLRRK2 Promotes Tau Accumulation, Aggregation and Release
Guerreiro, P. S., Gerhardt, E., da Fonseca, T. L., Bähr, M., Outeiro, T. F., & Eckermann, K. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9209-z · Cited by 46
α-Synuclein: A potent inducer of tau pathology
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Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?
Brembati, V., Faustini, G., Longhena, F., & Bellucci, A. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1197853 · Cited by 43
“This part of the protein reduces the NAC propensity for aggregation, mediates the majority of α-Syn interactions with proteins, metal ions and other ligands, including dopamine and polyamines, and harbors the majority of PTMs sites (Jensen et al., 1999; Paik et al., 1999; Giasson et al., 2003; Fernandez et al., 2004;…”
BackgroundIs tau ready for admission to the prion club?
Hall, G. F., & Patuto, B. A. (2012) · Prion · doi:10.4161/pri.19912 · Cited by 43
“, Asyn(132)) that are known to have effects on tau conformation and MT-binding.(8) This may also account for the disproportionate presence of specific tau isoforms (i.”
BackgroundDe Novo Design of Self-Assembled Hexapeptides as β-Amyloid (Aβ) Peptide Inhibitors
Wang, Q., Liang, G., Zhang, M., Zhao, J. W., Patel, K., Yu, X., Zhao, C., Ding, B., Zhang, G., Zhou, F., et al. (2014) · ACS Chemical Neuroscience · doi:10.1021/cn500165s · Cited by 43
Uchihara, T., Nakamura, A., Mochizuki, Y., Hayashi, M., Orimo, S., Isozaki, E., & Mizutani, T. (2005) · Acta Neuropathologica · doi:10.1007/s00401-005-1044-2 · Cited by 42
“Moreover, colocalization of a-synuclein and tau epitopes is frequent in various degenerative processes [1], and these two proteins may interact during the formation of aggregates [9].”
BackgroundUnderstanding co-polymerization in amyloid formation by direct observation of mixed oligomers
Young, L. M., Tu, L., Raleigh, D. P., Ashcroft, A. E., & Radford, S. E. (2017) · Chemical Science · doi:10.1039/c7sc00620a · Cited by 41
Sukhanova, A. V., Poly, S., Bozrova, S. V., Lambert, É., Ewald, M., Karaulov, A. V., Molinari, M., & Nabiev, I. R. (2019) · Frontiers in Chemistry · doi:10.3389/fchem.2019.00480 · Cited by 42
“For example, heavy-chain amyloidosis is accounted for by accumulation of immunoglobulin aggregations, and PD is related to intracellular aggregation of α-synuclein (Giasson et al., 2003).”
BackgroundCommon variants in PARK loci and related genes and Parkinson's disease
Chung, S. J., Armasu, S. M., Biernacka, J. M., Lesnick, T. G., Rider, D. N., Lincoln, S., Soto‐Ortolaza, A. I., Farrer, M. J., Cunningham, J. M., Rocca, W. A., et al. (2010) · Movement Disorders · doi:10.1002/mds.23376 · Cited by 42
“zygous for the H1 haplotype express higher levels of the tau protein,(42) and tau overexpression may promote fibrillization of the alpha-synuclein protein.(43) Although the most significant finding for SNCA (SNP rs2736990) and PD susceptibility lost significance after correction for multiple testing, the SNP is locate…”
BackgroundDementia with Lewy Bodies: Molecular Pathogenesis and Implications for Classification
Cummings, J. L. (2004) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/0891988704267473 · Cited by 42
“Similarly, alpha synuclein induces fibrillization of tau protein, suggesting that the accumulation of alpha synuclein or hyperphosphorylated tau can promote the pathological processing of the other.(31) Studies with triple transgenic mice reveal that amyloid deposition precedes tangle formation, indicating that the ac…”
BackgroundTerni, B., Rey, M. J., Boluda, S., Torrejón-Escribano, B., Sabate, M. P., Calopa, M., van Leeuwen, F. W., & Ferrer, I. (2007) · Acta Neuropathologica · doi:10.1007/s00401-006-0192-3 · Cited by 42
“Yet the co-localization of the two proteins has also been demonstrated in a limited number of diseased brains [ 18 , 31].”
BackgroundInfluentialThe role of α-synuclein and tau in neurodegenerative movement disorders
Wenning, G. K., & Jellinger, K. A. (2005) · Current Opinion in Neurology · doi:10.1097/01.wco.0000168241.53853.32 · Cited by 42
The α-synuclein burden hypothesis of Parkinson disease and its relationship to Alzheimer disease
McGeer, P. L., & McGeer, E. G. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2008.04.008 · Cited by 41
“taken as confirmation of previous studies of synergistic fibrillization of tau and αSyn (Giasson et al., 2003; Lee et al., 2004).”
Result
Metadata
- Authors
- Giasson, B. I., Forman, M. S., Higuchi, M., Golbe, L. I., Graves, C. L., Kotzbauer, P. T., Trojanowski, J. Q., & Lee, V. M.-Y.
- Affiliations
- University of Medicine and Dentistry of New Jersey (US)
- Corresponding author
- Lee, Virginia M.-Y.
- ORCID
- Venue
- Science
- Published
- 2003-04-25
- Volume
- 300
- Issue
- 5619
- Pages
- 636-640
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2073893553
- Cited by
- 879
- References
- 27
- Citations by year
- 2026: 23 · 2025: 29 · 2024: 37 · 2023: 35 · 2022: 58 · 2021: 32 · 2020: 50 · 2019: 52 · 2018: 49 · 2017: 42 · 2016: 35 · 2015: 31 · 2014: 39 · 2013: 42 · 2012: 33
- FWCI
- 26.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- alpha-synuclein, tau protein, amyloid fibril formation, protein aggregation, neurodegenerative diseases, synucleinopathies, tauopathy, oligodendrocytes, P301L tau, A53T alpha-synuclein, transgenic mouse model, intraneuronal inclusions
- MeSH terms
- Amyloid, Animals, Biopolymers, Brain Chemistry, Humans, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Microscopy, Fluorescence, Nerve Tissue Proteins, Neurons, Oligodendroglia, Protein Conformation, Microscopy, Immunoelectron, tau Proteins, Neurodegenerative Diseases, Protein Isoforms, Tauopathies, Mice, Synucleins, alpha-Synuclein
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