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 tau protein and α-synuclein can directly interact promoting their co-assembly.
“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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“In a mouse line expressing P301L tau in oligodendrocytes, co-expression of mutant human a -synuclein resulted in the appearance of thioflavin S-positive staining that was not observed in the single transgenic lines [130].”
BackgroundKovács, G. G., Milenković, I., Wöehrer, A., Höftberger, R., Gelpí, E., Haberler, C., Hönigschnabl, S., Reiner‐Concin, A., Heinzl, H., Jungwirth, S., et al. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1157-y · Cited by 360 · see citing works
“1 3 It has been hypothesised that Aβ, tau, and α-synuclein mutually promote their accumulation [17, 33].”
BackgroundNeurodegenerative disorders associated with diabetes mellitus
Ristow, M. (2004) · Journal of Molecular Medicine · doi:10.1007/s00109-004-0552-1 · Cited by 350 · see citing works
“Recent evidence suggests that PD is a filamentous disorder (as in Alzheimer and Huntington disease) where neuronal deposits of microfibrils made of aberrent a-synuclein and tau proteins synergize [243].”
BackgroundThe Oxidation State of DJ-1 Regulates its Chaperone Activity Toward α-Synuclein
Zhou, W., Zhu, M., Wilson, M. A., Petsko, G. A., & Fink, A. L. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.12.030 · Cited by 350 · see citing works
Oueslati, A., Fournier, M., & Lashuel, H. A. (2010) · Progress in brain research · doi:10.1016/s0079-6123(10)83007-9 · Cited by 340 · see citing works
Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration
Tracy, T. E., Madero‐Pérez, J., Swaney, D. L., Chang, T. S., Moritz, M., Konràd, C., Ward, M. E., Stevenson, E. J., Hüttenhain, R., Kauwe, G., et al. (2022) · Cell · doi:10.1016/j.cell.2021.12.041 · Cited by 347 · see citing works
“We detected domain-specific biotinylation sites on SNARE complex and synaptic vesicle proteins (Figure 3D; Table S2) and the known interaction between Tau and a-synuclein (Giasson et al., 2003).”
Self-citationThe Epidemiology of Dementia Associated with Parkinson's Disease
Aarsland, D., & Kurz, M. W. (2010) · Brain Pathology · doi:10.1111/j.1750-3639.2009.00369.x · Cited by 340 · see citing works
“Interestingly, a gene–gene interaction between MAPT and SNCA (31), co-localization of alpha-synuclein and tau protein within the Lewy bodies in PD (43) and synergistic fibrillization observed in vitro (30) were also reported.”
BackgroundNeuropathological spectrum of synucleinopathies
Jellinger, K. A. (2003) · Movement Disorders · doi:10.1002/mds.10557 · Cited by 338 · see citing works
Functional AmyloidsPreprint
Otzen, D. E., & Riek, R. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a033860 · Cited by 332 · see citing works
“Specific coaggregation of some hormones might be possible (Maji et al. 2009b) because amyloid peptides are able to cross-seed (Han et al. 1995; Giasson et al. 2003), which would also eventually result in a defined hormone release ratio.”
BackgroundAlzheimer Disease With Amygdala Lewy Bodies: A Distinct Form of α-Synucleinopathy
Uchikado, H., Lin, W.-L., DeLucia, M. W., & Dickson, D. W. (2006) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/01.jnen.0000225908.90052.07 · Cited by 359 · see citing works
“Giasson et al pointed out that tau and >-synuclein may reciprocally promote aggregation in vitro (42).”
BackgroundExosomes: Mediators of Neurodegeneration, Neuroprotection and Therapeutics
Kalani, A., Tyagi, A. A., & Tyagi, N. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8544-1 · Cited by 333 · see citing works
“Tau protein which is involved in the pathogenesis of Alzheimer’s disease can accelerate exosome-mediated release of α-syn toxin from injured neurons as it can interact with α-syn, promoting oligomerization and toxicity of these proteins [72].”
BackgroundPaleologou, K. E., Oueslati, A., Shakked, G., Rospigliosi, C. C., Kim, H., Lamberto, G. R., Fernández, C. O., Schmid, A. W., Chegini, F., Gai, W., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.5922-09.2010 · Cited by 324 · see citing works
“The C-terminal region of -syn has been implicated in the majority of -syn interactions with proteins (Jensen et al., 1999; Giasson et al., 2003; Fernández et al., 2004) and metal ions (Paik et al.”
BackgroundPreparation and Characterization of Neurotoxic Tau Oligomers
Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Guerrero-Muñoz, M. J., Jackson, G. R., & Kayed, R. (2010) · Biochemistry · doi:10.1021/bi1016233 · Cited by 359 · see citing works
Mechanisms of secretion and spreading of pathological tau protein
Brunello, C. A., Merezhko, M., Uronen, R.-L., & Huttunen, H. J. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03349-1 · Cited by 304 · see citing works
Yazawa, I., Giasson, B. I., Sasaki, R., Zhang, B., Joyce, S., Uryu, K., Trojanowski, J. Q., & Lee, V. M.-Y. (2005) · Neuron · doi:10.1016/j.neuron.2005.01.032 · Cited by 301 · see citing works
Self-citationSengupta, U., & Kayed, R. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102270 · Cited by 303 · see citing works
“Several groups including ours demonstrated α-Syn/tau direct interaction forming aggregates reflecting cross-seeding mechanism in vitro (Gerson et al., 2018; Giasson et al., 2003; Hojjatian et al., 2021; Lasagna-Reeves et al., 2010; Sengupta et al., 2020).”
BackgroundOxidative Stress in Neurodegeneration
Shukla, V., Mishra, S. K., & Pant, H. C. (2011) · Advances in Pharmacological Sciences · doi:10.1155/2011/572634 · Cited by 292 · see citing works
Alpha-synuclein and tau: teammates in neurodegeneration?
Moussaud, S., Jones, D. R., Moussaud-Lamodière, E. L., Delenclos, M., Ross, O. A., & McLean, P. J. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-43 · Cited by 291 · see citing works
“Likewise, cognitive deficits and tauopathy have been observed in αsyn-overexpressing PD models [100-103].”
BackgroundInfluentialPrion-like disorders: blurring the divide between transmissibility and infectivity
Cushman-Nick, M., Johnson, B. S., King, O. D., Gitler, A. D., & Shorter, J. (2010) · Journal of Cell Science · doi:10.1242/jcs.051672 · Cited by 288 · see citing works
“composed singly of tau or -synuclein, except for a few instances in which spatially segregated portions of a fiber were labeled positive for either tau or -synuclein (Giasson et al., 2003a).”
BackgroundInfluentialHead injury and Parkinson's disease risk in twins
Goldman, S. M., Tanner, C. M., Oakes, D., Bhudhikanok, G. S., Gupta, A., & Langston, J. W. (2006) · Annals of Neurology · doi:10.1002/ana.20882 · Cited by 289 · see citing works
Wacker, J. L., Zareie, M. H., Fong, H. K., Sarıkaya, M., & Muchowski, P. J. (2004) · Nature Structural & Molecular Biology · doi:10.1038/nsmb860 · Cited by 284 · see citing works
Tsigelny, I. F., Crews, L., Desplats, P., Shaked, G. M., Sharikov, Y., Mizuno, H., Spencer, B., Rockenstein, E., Trejo, M., Platoshyn, O., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003135 · Cited by 281 · see citing works
“abnormal conditions [91].”
RetractedRecent advances in our understanding of neurodegeneration
Jellinger, K. A. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-009-0240-y · Cited by 274 · see citing works
“The mechanism by which aSyn, tau, and Ab protein make fibrils is an example of conformational plasticity, because these polypeptides can visit a coil or helical structure, but otherwise they convert into a pathogenic b-sheet structure highly suitable for polymerization and fiber formation (Cairns et al. 2004; Cookson…”
BackgroundIntegrating Pathways of Parkinson's Disease in a Molecular Interaction Map
Fujita, K., Ostaszewski, M., Matsuoka, Y., Ghosh, S., Glaab, E., Trefois, C., Crespo, I., Perumal, T. M., Jurkowski, W., Antony, P. M. A., et al. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8489-4 · Cited by 270 · see citing works
“Axonal transport might be impaired by misfolded α-syn through perturbation of microtubule assembly [135–137], especially together with MAPT protein [138–143].”
BackgroundTemplate-assisted filament growth by parallel stacking of tau
Margittai, M., & Langen, R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401911101 · Cited by 276 · see citing works
The neuropathology, pathophysiology and genetics of multiple system atrophy
Ahmed, Z., Asi, Y. T., Sailer, A., Lees, A. J., Houlden, H., Révész, T., & Holton, J. L. (2011) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2011.01234.x · Cited by 267 · see citing works
Tau and α‐synuclein in susceptibility to, and dementia in, Parkinson's disease
Goris, A., Williams‐Gray, C. H., Clark, G. R., Foltynie, T., Lewis, S. J. G., Brown, J., Ban, M., Spillantini, M. G., Compston, A., Burn, D. J., et al. (2007) · Annals of Neurology · doi:10.1002/ana.21192 · Cited by 270 · see citing works
“In vitro experiments have demonstrated that -synuclein is able to initiate tau fibrillization, after which -synuclein and tau synergistically promote fibrillization.(43) Our findings of an interaction between SNCA and MAPT increasing risk for idiopathic PD lend further support to the intersection of the tau and -synuc…”
BackgroundPrevalence and impact of vascular and Alzheimer pathologies in Lewy body disease
Jellinger, K. A., & Attems, J. (2008) · Acta Neuropathologica · doi:10.1007/s00401-008-0347-5 · Cited by 266 · see citing works
“... disorders [57, 78], and the association between dopaminergic neuronal degeneration, accumulation of Syn and tau or both proteins in LRRK2 mutations [1, 29, 102], induction of hyperphosphorylation of tau by Syn in the MPTP model of parkinsonism [23], and the association of atypical protein kinase C (aPKC) and phosp…”
BackgroundInterface between tauopathies and synucleinopathies: A tale of two proteins
Galpern, W. R., & Lang, A. E. (2006) · Annals of Neurology · doi:10.1002/ana.20819 · Cited by 263 · see citing works
“Mice overexpressing human A53T SNCA not only demonstrate inclusions that stain for AS, but also have inclusions that stain for tau, and indeed some of the inclusions stain for both proteins.(120) Transgenic mice expressing both wild-type human SNCA and P301L mutant tau also demonstrate intracellular inclusions compose…”
BackgroundInfluentialGuo, J., Arai, T., Judith Miklossy, A., & McGeer, P. L. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509386103 · Cited by 261 · see citing works
Lewy body-related ?-synucleinopathy in the aged human brain
Jellinger, K. A. (2004) · Journal of Neural Transmission · doi:10.1007/s00702-004-0138-7 · Cited by 256 · see citing works
Sardi, S. P., Clarke, J. L., Viel, C., Chan, M., Tamsett, T. J., Treleaven, C. M., Bu, J., Sweet, L., Passini, M. A., Dodge, J. C., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220464110 · Cited by 252 · see citing works
“However, the disease mechanisms need further clarification, because α-synuclein fibrils may be able to promote the polymerization of tau (24, 38), so the observed tau aggregation in the CNS of Gba1 mice may be occurring secondary to α-synuclein fibrillation.”
BackgroundBassil, F., Brown, H. J., Pattabhiraman, S., Iwasyk, J. E., Maghames, C. M., Meymand, E. S., Cox, T. O., Riddle, D. M., Zhang, B., Trojanowski, J. Q., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.10.010 · Cited by 243 · see citing works
“First, Aβ plaques induce pooling of α-syn within the synaptic terminals which is “primed” to cross-seed other aggregation prone proteins like tau (Giasson et al., 2003; Guo et al., 2013).”
InfluentialSelf-citationHeat Shock Prevents Alpha-synuclein-induced Apoptosis in a Yeast Model of Parkinson's Disease
Flower, T. R., Chesnokova, L. S., Froelich, C. A., Dixon, C., & Witt, S. N. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.06.060 · Cited by 239 · see citing works
The natural history of treated Parkinson's disease in an incident, community based cohort
Evans, J., Mason, S., Williams‐Gray, C. H., Foltynie, T., Brayne, C., Robbins, T. W., & Barker, R. (2011) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2011.240366 · Cited by 235 · see citing works
Protein phosphorylation in neurodegeneration: friend or foe?
Tenreiro, S., Eckermann, K., & Outeiro, T. F. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00042 · Cited by 252 · see citing works
“Glycogen synthase kinase-3β (GSK-3β) activation was proposed as mediator of Aβ42 oligomer-induced effects on tau phosphorylation in P301L mice (Selenica et al., 2013).”
BackgroundInfluentialA critical evaluation of current staging of α-synuclein pathology in Lewy body disorders
Jellinger, K. A. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.07.006 · Cited by 229 · see citing works
“, in LRRK2 mutations [144] and in animal models of PD [145], with association of phospo-tau and αSyn in both NFTs and LBs [146] and in vitro promotion of tau aggregation by αSyn and vice versa [147].”
BackgroundA critical reappraisal of current staging of Lewy-related pathology in human brain
Jellinger, K. A. (2008) · Acta Neuropathologica · doi:10.1007/s00401-008-0406-y · Cited by 229 · see citing works
The Role of Insulin/IGF-1/PI3K/Akt/GSK3β Signaling in Parkinson's Disease Dementia
Yang, L., Wang, H., Liu, L., & Xie, A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00073 · Cited by 228 · see citing works
“On one hand, low concentrations of α-synuclein do not fibrillate until tau is present (Giasson et al., 2003).”
BackgroundCholesterol homeostasis in neurons and glial cells
Vance, J. E., Hayashi, H., & Karten, B. (2005) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2005.01.005 · Cited by 222 · see citing works
Initiative, T. P. P. M., Kang, J., Mollenhauer, B., Coffey, C. S., Toledo, J. B., Weintraub, D. A., Galasko, D. R., Irwin, D. J., Deerlin, V. M. V., Chen‐Plotkin, A. S., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1552-2 · Cited by 225 · see citing works
“Basic research and neuropathology studies have suggested interaction between α-syn and tau in the brain [7, 8, 10, 43], which are further supported by our findings of a significant correlation between CSF α-syn and tau.”
Self-citationNeurogenesis in aging and age-related neurodegenerative diseases
Čulig, L., Chu, X., & Bohr, V. A. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101636 · Cited by 229 · see citing works
Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies
Sinsky, J., Pichlerova, K., & Hanes, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179207 · Cited by 220 · see citing works
“The tau subsequently aggregates which could promote the pathological pathway in synergy [542,543].”
BackgroundCerebrospinal fluid biomarkers in Parkinson disease
Parnetti, L., Castrioto, A., Chiasserini, D., Persichetti, E., Tambasco, N., El-Agnaf, O., & Calabresi, P. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.10 · Cited by 209 · see citing works
Aβ deposition is associated with enhanced cortical α-synuclein lesions in Lewy body diseases
Pletniková, O., West, N. C., Lee, M. K., Rudow, G. L., Skolasky, R. L., Dawson, T. M., Marsh, L., & Troncoso, J. C. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.10.006 · Cited by 209 · see citing works
α-Synuclein: Normal Function and Role in Neurodegenerative Diseases
Norris, E. H., Giasson, B. I., & Lee, V. M. ‐. (2004) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(04)60002-0 · Cited by 202 · see citing works
Self-citationGlucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models
Sardi, S. P., Viel, C., Clarke, J., Treleaven, C. M., Richards, A. M., Park, H., Olszewski, M. A., Dodge, J. C., Marshall, J., Makino, E., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1616152114 · Cited by 203 · see citing works
- 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
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › 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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