Cited by 249Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

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Uchihara, Toshiki, Giasson, Benoit I.·2016·Acta Neuropathologica

DOI 10.1007/s00401-015-1485-1PMC PMC4698305

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Abstract

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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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.
ORCID: Uchihara, Toshiki
Giasson, Benoit I.
Venue: Acta Neuropathologica
Publisher: Springer Science and Business Media LLC
Published: 2015-10-07
Volume: 131
Issue: 1
Pages: 49-73
ISSN: 0001-6322 (ISSN-L)
1432-0533
DOI: 10.1007/s00401-015-1485-1
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
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
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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Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

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