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Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage
Abstract
The presence of Lewy bodies, mainly consisting of aggregated α-synuclein, is a pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The α-synuclein inclusions are predominantly found in neurons, but also appear frequently in astrocytes. However, the pathological significance of α-synuclein inclusions in astrocytes and the capacity of glial cells to clear toxic α-synuclein species remain unknown. In the present study we investigated uptake, degradation and toxic effects of oligomeric α-synuclein in a co-culture system of primary neurons, astrocytes and oligodendrocytes. Alpha-synuclein oligomers were found to co-localize with the glial cells and the astrocytes were found to internalize particularly large amounts of the protein. Following ingestion, the astrocytes started to degrade the oligomers via the lysosomal pathway but, due to incomplete digestion, large intracellular deposits remained. Moreover, the astrocytes displayed mitochondrial abnormalities. Taken together, our data indicate that astrocytes play an important role in the clearance of toxic α-synuclein species from the extracellular space. However, when their degrading capacity is overburdened, α-synuclein deposits can persist and result in detrimental cellular processes.
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“The αSYN and Aβ accumulation result in severe cellular stress, indicated by lysosomal and mitochondrial deficiencies [11, 12, 23].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [23]
In the citing paper
“The concentrations were selected based on our previous studies [11, 12, 23, 28, 29].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [23]
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“We have previously shown that astrocytes accumulate large amounts of αSYN and Aβ aggregates, resulting in severe cellular stress [11, 12, 23, 24].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [23]
In the citing paper
“In the context of neurodegeneration, astrocytes take up aggregate-prone MAPT/tau, amyloid beta (Aβ) and SNCA (synuclein alpha), and degrade these proteins through autophagy [407–412].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [412]
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Cited by
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Background
Metadata
- Authors
- Lindström, V., Gustafsson, G., Sanders, L. H., Howlett, E. H., Sigvardson, J., Kasrayan, A., Ingelsson, M., Bergström, J., & Erlandsson, A.
- Affiliations
- Uppsala University (SE)
- University of Pittsburgh (US)
- BioArctic Neuroscience (Sweden) (SE)
- Corresponding author
- Lindström, Veronica
- Venue
- Molecular and Cellular Neuroscience
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 82
- Pages
- 143-156
- ISSN
- 1044-7431 (ISSN-L)
- OpenAlex
- W2609846517
- Cited by
- 233
- References
- 50
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 32 · 2023: 22 · 2022: 21 · 2021: 31 · 2020: 38 · 2019: 24 · 2018: 18 · 2017: 9
- FWCI
- 16.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- alpha-synuclein oligomers, astrocytes, Lewy bodies, Parkinson's disease, dementia with Lewy bodies, lysosomal degradation, mitochondrial damage, neurodegeneration
- MeSH terms
- Animals, Astrocytes, Cytoplasm, Mice, Inbred C57BL, Mitochondria, Neurons, Oligodendroglia, Parkinson Disease, Lewy Bodies, Coculture Techniques, Intracellular Space, alpha-Synuclein
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