α-Synuclein strains cause distinct synucleinopathies after local and systemic administration
Open accessAbstract
Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions. The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton α-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial α-synuclein (α-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal α-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies. The discovery of α-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies. In this study we show that α-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined α-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that α-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that α-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct α-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.
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Alpha-synuclein crossing the blood-brain barrier bidirectionally could signify an important contributory event in Parkinson's disease pathogenesis.
“which could signify an important contributory event in PD pathogenesis (469, 563).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [469]
In rodents, alpha-synuclein injected intraventricularly undergoes brain-to-blood efflux, and injected intravenously undergoes blood-to-brain influx.
“Specifically, 𝛂 -syn injected intraventricularly and intravenously in rodents undergoes brain-to-blood efflux and blood-to-brain influx, respectively (469, 563).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [469]
Alpha-synuclein crosses the blood-brain barrier bidirectionally.
“Recent studies reveal that 𝛂 -syn crosses the BBB bidirectionally, which could signify an important contributory event in PD pathogenesis (469, 563).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [469]
Systemically administered alpha-synuclein oligomers, ribbons, and fibrils cross the blood-brain barrier into the brain, where alpha-synuclein amplification and strain-specific pathology and neurotoxic phenotypes are observed.
“Administered systemically, 𝛂 -syn oligomers, ribbons, and fibrils crossed the BBB into the brain, where 𝛂 -syn amplification and strain-specific pathology and neurotoxic phenotypes are observed (469).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [469]
After local and systemic injections, α-synuclein strains can induce distinct synucleinopathies with varying levels of toxicity and behavioral phenotypes.
“after local and systemic injections, α‐synuclein strains can also induce distinct synucleinopathies with varying levels of toxicity and behavioral phenotypes.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [171]
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- Authors
- Peelaerts, W., Bousset, L., Van der Perren, A., Moskalyuk, A., Pulizzi, R., Giugliano, M., Van den Haute, C., Melki, R., & Baekelandt, V.
- Affiliations
- KU Leuven (BE)
- Centre National de la Recherche Scientifique (FR)
- University of Antwerp (BE)
- Corresponding author
- Melki, R.
- Baekelandt, V.
- Venue
- Nature
- Published
- 2015-06
- Volume
- 522
- Issue
- 7556
- Pages
- 340-344
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2111216320
- Cited by
- 1,130
- References
- 36
- Citations by year
- 2026: 41 · 2025: 59 · 2024: 83 · 2023: 89 · 2022: 105 · 2021: 126 · 2020: 110 · 2019: 139 · 2018: 130 · 2017: 114 · 2016: 93 · 2015: 41
- FWCI
- 88.83
- Type
- journal article
- Language
- en
- Open access
- green
- infoscience.epfl.ch
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- SDL (submittedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-BSV8-0021, ANR-09-MNPS-0013)
- 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 strains, synucleinopathies, Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, protein aggregation, fibrils, ribbons, oligomers, blood-brain barrier penetration, neurotoxicity, motor impairment, intravenous injection, neurodegeneration
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Female, Humans, Parkinson Disease, Phenotype, Substantia Nigra, Synapses, Rats, Wistar, Multiple System Atrophy, Lewy Body Disease, Rats, alpha-Synuclein
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