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Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies
Open accessAbstract
Progressive aggregation of alpha-synuclein (αS) through formation of amorphous pale bodies to mature Lewy bodies or in neuronal processes as Lewy neurites may be the consequence of conformational protein changes and accumulations, which structurally represents "molecular template". Focal initiation and subsequent spread along anatomically connected structures embody "structural template". To investigate the hypothesis that both processes might be closely associated and involved in the progression of αS pathology, which can be observed in human brains, αS amyloidogenic precursors termed "seeds" were experimentally injected into the brain or peripheral nervous system of animals. Although these studies showed that αS amyloidogenic seeds can induce αS pathology, which can spread in the nervous system, the findings are still not unequivocal in demonstrating predominant transsynaptic or intraneuronal spreads either in anterograde or retrograde directions. Interpretation of some of these studies is further complicated by other concurrent aberrant processes including neuroimmune activation, injury responses and/or general perturbation of proteostasis. In human brain, αS deposition and neuronal degeneration are accentuated in distal axon/synapse. Hyperbranching of axons is an anatomical commonality of Lewy-prone systems, providing a structural basis for abundance in distal axons and synaptic terminals. This neuroanatomical feature also can contribute to such distal accentuation of vulnerability in neuronal demise and the formation of αS inclusion pathology. Although retrograde progression of αS aggregation in hyperbranching axons may be a consistent feature of Lewy pathology, the regional distribution and gradient of Lewy pathology are not necessarily compatible with a predictable pattern such as upward progression from lower brainstem to cerebral cortex. Furthermore, "focal Lewy body disease" with the specific isolated involvement of autonomic, olfactory or cardiac systems suggests that spread of αS pathology is not always consistent. In many instances, the regional variability of Lewy pathology in human brain cannot be explained by a unified hypothesis such as transsynaptic spread. Thus, the distribution of Lewy pathology in human brain may be better explained by variable combinations of independent focal Lewy pathology to generate "multifocal Lewy body disease" that could be coupled with selective but variable neuroanatomical spread of αS pathology. More flexible models are warranted to take into account the relative propensity to develop Lewy pathology in different Lewy-prone systems, even without interconnections, compatible with the expanding clinicopathological spectra of Lewy-related disorders. These revised models are useful to better understand the mechanisms underlying the variable progression of Lewy body diseases so that diagnostic and therapeutic strategies are improved.
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“In the human brain, synuclein deposition and neuronal degeneration are accentuated in distal regions23.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [23]
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Staging of brain pathology related to sporadic Parkinson’s disease
Braak, H., Tredici, K. D., Rüb, U., de Vos, R. A. I., Jansen Steur, E. N. H., & Braak, E. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00065-9 · Cited by 10,777
Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997) · Nature · doi:10.1038/42166 · Cited by 8,382
Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. (1997) · Science · doi:10.1126/science.276.5321.2045 · Cited by 8,240
α-Synuclein Locus Triplication Causes Parkinson's Disease
Singleton, A. B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R., et al. (2003) · Science · doi:10.1126/science.1090278 · Cited by 4,383
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., & Glabe, C. G. (2003) · Science · doi:10.1126/science.1079469 · Cited by 4,064
AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
Krüger, R., Kuhn, W., Müller, T., Woitalla, D., Graeber, M., Kösel, S., Przuntek, H., Epplen, J. T., Schols, L., & Riess, O. (1998) · Nature Genetics · doi:10.1038/ng0298-106 · Cited by 3,836
The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia
Zarranz, J. J., Alegre, J., Gómez‐Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., Vidal, L., Hoenicka, J., Rodriguez, O., Atarés, B., et al. (2004) · Annals of Neurology · doi:10.1002/ana.10795 · Cited by 2,737
Luk, K. C., Kehm, V., Carroll, J., Zhang, B., O’Brien, P., Trojanowski, J. Q., & Lee, V. M.-Y. (2012) · Science · doi:10.1126/science.1227157 · Cited by 2,563
α-Synuclein is phosphorylated in synucleinopathy lesions
Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M. S., Shen, J., Takio, K., & Iwatsubo, T. (2002) · Nature Cell Biology · doi:10.1038/ncb748 · Cited by 2,174
α-synuclein locus duplication as a cause of familial Parkinson's disease
Chartier-Harlin, M.-C., Kachergus, J., Roumier, C., Mouroux, V., Douay, X., Lincoln, S., Levecque, C., Larvor, L., Andrieux, J., Hulihan, M., et al. (2004) · The Lancet · doi:10.1016/s0140-6736(04)17103-1 · Cited by 2,029
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Self-citationDagra, A., Miller, D. R., Shaerzadeh, F., Lin, M., Gopinath, A., Harris, S., Sorrentino, Z. A., Velasco, S., Alonge, A. R., Azar, J., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.30.437775 · Cited by 1
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Giorgi, F. D., Letourneur, Æ., Kashyrina, M., Zinghirino, F., Doveró, S., Dutheil, N., Largitte, L.-A., Arotçarena, M.-L., Bézard, E., Canron, M., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-3921168/v1 · Cited by 1
Theologidis, V., Ferreira, S. A., Jensen, N. M., Moreira, D. G., Ahlgreen, O. A., Hansen, M. W., Rosenberg, E. D., Richner, M., Faress, I. M. G., Gram, H., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.05.610956 · Cited by 1
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Homma, T. (2017) · Journal of Nihon University Medical Association · doi:10.4264/numa.76.5_235
Uchihara, T., & Toru, S. (2018) · Neurology · doi:10.1212/wnl.0000000000004915
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Haack, J. F. (2021) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-8398
Ye, Z., Long, L., Long, S., Yang, M., & Tan, M. (2023) · Materials Express · doi:10.1166/mex.2023.2502
Patton, T., Comini, G., Narasimhan, K., Cairns, A. G., Ådén, J., Almqvist, F., Bemelmans, A., Brouillet, E., McKernan, D. P., & Dowd, E. (2024) · doi:10.22541/au.171475235.57509359/v1
Ione, A. (2024) · Springer eBooks · doi:10.1007/978-3-031-55440-7_1
Patton, T., Comini, G., Narasimhan, K., Cairns, A. G., Ådén, J., Almqvist, F., Bemelmans, A., Brouillet, E., McKernan, D. P., & Dowd, E. (2024) · European Journal of Neuroscience · doi:10.1111/ejn.16493
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Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891216
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Khalafi, P., Vogel, J. W., Boghammer, P., Raunio, A., Kivistö, V., Savola, S. E., Kok, E., Mikhailenko, E., Myllykangas, L., & Dagher, A. (2026) · medRxiv · doi:10.64898/2026.01.13.26343943
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Metadata
- Authors
- Uchihara, T., & Giasson, B. I.
- Affiliations
- Tokyo Metropolitan Institute of Medical Science (JP)
- University of Florida (US)
- Corresponding author
- Uchihara, Toshiki
- Giasson, Benoit I.
- Venue
- Acta Neuropathologica
- Published
- 2015-10-07
- Volume
- 131
- Issue
- 1
- Pages
- 49-73
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC4698305
- OpenAlex
- W1854508876
- Cited by
- 249
- References
- 203
- Citations by year
- 2026: 8 · 2025: 21 · 2024: 37 · 2023: 19 · 2022: 24 · 2021: 28 · 2020: 28 · 2019: 22 · 2018: 27 · 2017: 23 · 2016: 10 · 2015: 2
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (25430057)
- Japan foundation for Neuroscience and Mental Health
- Mitsui Life Social Welfare Foundation
- Tokyo Metropolitan Institute of Medical Science
- National Institute of Neurological Disorders and Stroke (NS089622)
- National Parkinson Foundation (NPF-UN203)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, Lewy bodies, Lewy neurites, neurodegeneration, neuroimmune activation, proteostasis, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, synucleinopathies, neuroinflammation
- MeSH terms
- Animals, Axons, Brain, Humans, Parkinson Disease, Lewy Bodies, Lewy Body Disease, alpha-Synuclein
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