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.
“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]
The concentrations of αSYN-F and Aβ-F used were selected based on previous studies.
“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]
Astrocytes accumulate large amounts of αSYN and Aβ aggregates, resulting in severe cellular stress.
“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 context of neurodegeneration, astrocytes take up aggregate-prone MAPT/tau, amyloid beta (Aβ) and SNCA (synuclein alpha), and degrade these proteins through autophagy.
“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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Import and Export of Misfolded α-Synuclein
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Targeted attenuation of elevated histone marks at SNCA alleviates α‐synuclein in Parkinson's disease
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“It is known that astrocyte and other glial cells scavenge extracellular a -synuclein released from neurons (Lindstrom et al , 2017; Loria et al , 2017).”
Protein astrogliopathies in human neurodegenerative diseases and aging
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“…on whether or not the astrocytic uptake and processing of aSyn may have cytoprotective (Hua et al., 2019; Lindstrom et al., 2017; Loria et al., 2017) or cytotoxic (Braidy et al., 2013; Cavaliere et al., 2017; H.-J. Lee et al., 2010b; Lindstrom et al., 2017; Rostami et al., 2017) consequences.”
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“Reactive astrocytes in ischemia exhibited a phenotype that might be beneficial or protective (A2), whereas reactive astrocytes induced by LPS exhibited a phenotype that might be detrimental (A1) (Zamanian et al., 2012; Lindstrom et al., 2017).”
BackgroundAlpha-Synuclein as a Prominent Actor in the Inflammatory Synaptopathy of Parkinson’s Disease
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“Whilst the mechanisms underlying the astrocytic uptake of α -Syn remain to be fully elucidated, oligomeric α -Syn is rapidly internalised by astrocytes in vitro 58,59 .”
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“Furthermore, it has been shown that cultured astrocytes take up oligomeric alpha-synuclein, however, an excess of it can lead to mitochondrial damage and impaired lysosomal degradation, with consequent accumulation of the protein (Lindström et al., 2017).”
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Suppression of astrocytic autophagy by αB-crystallin contributes to α-synuclein inclusion formation
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“For instance, the accumulation of α-synuclein induces astrocytic mitochondrial impairments [4].”
InfluentialAlpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease
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“Subsequently, autophagy is suppressed, which causes severe damage to mitochondria and sensitizes astrocytes to apoptosis; this results in the exacerbation of neurodegeneration [311,314,315].”
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“This astrocyte pathology may represent the seeding of inclusion formation within astrocytes, as occurs in neurons, or may be the result of phagocytic activity by these cell types that are clearing debris from stressed or dying inclusion-bearing neurons [1, 38, 41, 87].”
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“It is known that Ca2+ dynamics modulate mitochondrial dynamics in astrocytes (Jackson & Robinson, 2015), whereas α-synuclein disturbs the function and morphology of mitochondria (Gustafsson et al., 2017; Lindstrom et al., 2017).”
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“Other studies confirm that α-synuclein associates with mitochondria affecting its dynamics and functioning, but its role remains to be established [280, 281].”
BackgroundProtein aggregation and its affecting mechanisms in neurodegenerative diseases
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“Moreover, α -Syn aggregates in astrocytes have been found in DLB and PD, which compromise lysosomal autophagy and degradation, leading to mitochondrial dysfunction in these cells (Lindstr ¨ om et al., 2017; Sorrentino et al., 2019).”
BackgroundDifferent pattern of CSF glial markers between dementia with Lewy bodies and Alzheimer’s disease
Morenas‐Rodríguez, E., Alcolea, D. A., Suárez‐Calvet, M., Muñoz, L., Vilaplana, E., Sala, I., Subirana, A., Querol‐Vilaseca, M., Carmona‐Iragui, M., Illán‐Gala, I., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-44173-8 · Cited by 58 · see citing works
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“evoked mitochondrial abnormalities leading to cellular degeneration and death.[46,47] More recently, oligomeric αSwas reported to interact”
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“34,35 α-synuclein 124–127 Apparently, this induces the unfolded protein response, 123 mitochondrial impairment, 126 upregulation of major histocompatibility complex genes, and secretion of pro-inflammatory cytokines.”
Brain clearance of protein aggregates: a close-up on astrocytes
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“This impairs the astrocytes’ capability to support neuronal metabo - lism and synaptic function [102, 140].”
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Neurons and Glia Interplay in α-Synucleinopathies
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“However, a bidirectional link between aSyn accumulation and the protein degradation machineries exists and extensive studies have been conducted to elucidate not only the manner of aberrant aSyn degradation in a-synucleinopathies, but also the impact of various aSyn conformations on UPS and ALP function.”
BackgroundInfluentialMitochondria and Antibiotics: For Good or for Evil?
Suarez-Rivero, J. M., Pastor‐Maldonado, C. J., Povea-Cabello, S., Álvarez-Córdoba, M., Villalón-García, I., Talaverón-Rey, M., Suárez-Carrillo, A., Munuera-Cabeza, M., & Sánchez-Alcázar, J. A. (2021) · Biomolecules · doi:10.3390/biom11071050 · Cited by 51 · see citing works
“Aggregated αSyn disrupts vesicular transport, impairing autophagy, causing mitochondrial dysfunction and affecting vesicle recycling, neuronal plasticity and synaptic integrity [183].”
BackgroundAssociation of Glial Activation and α-Synuclein Pathology in Parkinson’s Disease
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Extracellular clusterin limits the uptake of α‐synuclein fibrils by murine and human astrocytes
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“Toxic species of α-synuclein can be efficiently internalized by astrocytes and degraded through the endo-lysosomal pathway (Lindström et al., 2017; Loria et al., 2017; Sacino et al., 2017).”
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“Due to incomplete digestion, intracellular α-syn deposits remained in the astrocytes, which resulted in a mitochondrial impairment [25].”
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“However, excessive α-synuclein uptake in glial cells can produce protein aggregates similar to those found in PD brains and trigger inflammatory responses, leading to the incorporation of fibrils into exosomes [118, 119].”
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Alpha-synuclein and the prion hypothesis in Parkinson's disease
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Astrocytic uptake of neuronal corpses promotes cell‐to‐cell spreading of tau pathology
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“This intracellular storage of pathological proteins results in severe cellular stress, indicated by lysosomal and mitochondrial deficiencies [11-16].”
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“…Figure 2Ai) and decrease the production neuroprotective canonical Wnt ligands by astrocytes (L’Episcopo et al., 2011, 2013, 2014; Okamoto et al., 2011; Lindström et al., 2017; Liu et al., 2018; Figure 2Aii; for an excellent review of the role of Wnt-signaling in neuron-microglia-astrocyte…”
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“It is reported that oligomeric α-synuclein may induce neurotoxicity by causing mitochondrial defects [30], membrane damage [31], autophagic and lysosomal dysfunction [32], endoplasmic reticulum stress [33], inflammatory responses [34], seeding and spreading [35] or synaptic dysfunction [36].”
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“2010a); furthermore, it has been shown that astrocytes extensively uptake aSO, resulting in sustained aSO intracellular deposits and mitochondrial dysfunction (Lindstrom et al. 2017).”
BackgroundGhrelin mediated neuroprotection - A possible therapy for Parkinson's disease?
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Lysosomal Functions in Glia Associated with Neurodegeneration
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“of α-synuclein has been associated with incessant intercellular deposits, thus instigating mitochondrial stress by over-burdening the lysosomal degradation pathway [89].”
BackgroundAstrocytes: The Stars in Neurodegeneration?
Dittlau, K. S., & Freude, K. (2024) · Biomolecules · doi:10.3390/biom14030289 · Cited by 38 · see citing works
“This mechanism is affected in PD, where both α -synuclein oligomers as well as mutations in the LRRK2 gene interfere with the astrocytic clearance of the aggregation burden [160,194].”
Extracellular alpha-synuclein: Sensors, receptors, and responses
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Glial cells in Parkinson´s disease: protective or deleterious?
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“Simplistically, there may exist a threshold that further affects mitochondrial integrity in astrocytes and then leads to neurotoxicity [215].”
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“patients [3, 161, 164] and in human derived astrocyte cultures [104, 162, 165-167].”
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The role of glia in Parkinson's disease: Emerging concepts and therapeutic applications
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The Role of Glial Mitochondria in α-Synuclein Toxicity
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“Lindstrom et al. (2017) tried to elucidate the clearance mechanism of toxic α-syn in glial cells.”
BackgroundInfluential
- 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 › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › 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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