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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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“Furthermore, in PD, excessive α-synuclein accumulation within astrocytes can damage astrocytic mitochondria, increase pro-inflammatory cytokine production and induce excitotoxicity through impairing astrocytic uptake of extracellular glutamate (Booth, Hirst, & WadeMartins, 2017; Gu et al., 2010; Lee et al., 2010; Lind…”
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“In PD, astrocyte uptake of α-synuclein aggregates also damages mitochondria 188 and disrupts ER–mitochondria Ca 2+ signalling 189 , potentially reducing energy output and promoting dopaminergic neuron loss.”
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“Autophagy in astrocytes is also critical for regulating the pathogenic consequences of ApoE4 [91]. overexpression of autophagy in astrocytes could modify the levels of a-synuclein and mitigate the toxicity imparted by the aggregation of a-synuclein on astrocytic and neuronal cells [92,93].”
BackgroundZombosomes are anucleated cell couriers that spread α-synuclein pathology
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“Multiple studies have shown that astrocytes clear extracellular α-syn [15, 30, 31, 33, 57, 60], thus they can mitigate α-syn spreading and preserve neurons from toxicity [33, 57].”
Immunotherapeutic interventions in Parkinson's disease: Focus on α-Synuclein
Ganguly, U., Singh, S., Chakrabarti, S., Saini, A. K., & Saini, R. V. (2022) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2021.11.010 · Cited by 6
Spencer, B. J., Schueler, A., Sung, D., & Rissman, R. A. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106942 · Cited by 4
“Neuroinflammation is a hallmark of AD and includes the proliferation of astrocytes as well as the activation of microglia cells (Alster et al., 2020; Amin et al., 2020; Bachiller et al., 2018; Guzman-Martinez et al., 2019; Lindstrom et al., 2017).”
Astrocytic lysosome deficits reduce alpha-synuclein degradation and induce the spread of pathology
Roth, L. M., Morozova, O., Stöhr, J., & Schapansky, J. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2026.107277 · Cited by 6
Curing the brain: in search for new astrocyte-specific therapies
Verkhratsky, A., Lee, C. J., Chun, H., Göritz, C., Harkany, T., Lee, J., Lee, S., Lindskog, M., Koh, W., Mulder, J., et al. (2026) · Experimental & Molecular Medicine · doi:10.1038/s12276-026-01712-4 · Cited by 8
“Protoplasmic astrocytes may accumulate and remove α -synuclein, thus exercising neuroprotection 211 , although overload with α - synuclein may cause mitochondrial damage while aggregated α - synuclein may spread through astrocytic syncytia 212,213 .”
Gupta, J., & Sashidhara, K. V. (2023) · European Journal of Medicinal Chemistry Reports · doi:10.1016/j.ejmcr.2023.100114 · Cited by 4
Novel and experimental therapeutics for the management of motor and non-motor Parkinsonian symptoms
Ullah, I., Wang, X., & Li, H. (2024) · Neurological Sciences · doi:10.1007/s10072-023-07278-7 · Cited by 4
“However, increased absorption of α-Syn oligomers caused insufficient protein degradation, the release of pro-inflammatory molecules, and mitochondrial dysfunction [23].”
Role of non-neuronal cells in neurorepair: a focus on proteinopathy and neurodegeneration
Rodríguez-Carreiro, S., Nogales, M. D. C., Jiménez-Galán, D., Carmona-Lorenzo, S., Caro-Martín, A., Navarro, E., & Esteras, N. (2024) · Regenerative medicine reports . · doi:10.4103/regenmed.regenmed-d-24-00005 · Cited by 2
Neurogliovascular alterations in brain pathologies across lifespan
Daigle, B., Bevilacqua, L. M., Noël, V. P., Lebel, M., Côté, D. C., Lévesque, L., & Ménard, C. (2024) · Glial health research. · doi:10.1016/j.ghres.2024.100004 · Cited by 4
Contribution of α‐synuclein cytopathologies to distinct seeding of misfolded α‐synuclein
Kim, A., Martínez-Valbuena, I., Danics, K., Forrest, S. L., & Kovács, G. G. (2025) · Brain Pathology · doi:10.1111/bpa.70024 · Cited by 3
“It is hypothesized that in the process of attempting to degrade the aggregates, some are stored, leading to the development of pathology [53 – 55].”
Harada, M., Masaki, K., Tanaka, T., Sekiya, H., Matsuse, D., Yamaguchi, H., Nishimura, Y., Takase, E. O., Tanaka, E., Kira, Y., et al. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02116-7 · Cited by 3
“Notably, the accumulation of α-syn deposits can induce a pro-inflammatory state in astrocytes and microglia, which leads to non-cell autonomous neuronal cell death [4, 17]. α-Syn reportedly opens astrocytic Cx43 HCs, thus releasing glutamate and ATP [9].”
The Influence of Striatal Astrocyte Dysfunction on Locomotor Activity in Dopamine-depleted Rats
Воронков, Д. Н., Stavrovskaya, A. V., Olshansky, A. S., Guschina, A. S., Худоерков, Р. М., & Illarioshkin, S. N. (2021) · Basic and Clinical Neuroscience Journal · doi:10.32598/bcn.2021.1923.1 · Cited by 2
“In PD, astrocytes accumulate toxic forms of α-synuclein and play a role in their propagation in the Central Nervous System (CNS) (Cavaliere et al., 2017; Lindström et al., 2017).”
BackgroundPaschou, C., Apokotou, O., Κόλλιας, Α., Charmpi, K., Dede, S., Samiotaki, M. K., Palese, F., Dimoula, K., Emmanouilidou, E., Taoufik, E., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.06.621638 · Cited by 2
Transgenic A53T Mice Have Astrocytic α‐Synuclein Aggregates in Dopamine and Striatal Regions
Peat, C., Prasad, A. A., Finkelstein, D. I., Sue, C. M., Johnston, J. A., Parish, C. L., Thompson, L. H., Kirik, D., & Halliday, G. M. (2026) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.70097 · Cited by 1
“This has only been observed previously in in vitro experiments where similar isolated α-synuclein puncta are found in around 40% of astrocytes after 24 h [32] with phagocytic accumulation of α-synuclein peaking at 48 h and the α-synuclein degraded by 170 h [31].”
Novello, C., Parati, M., Mazzetti, S., Rampoldi, O., Isilgan, H. B., Basellini, M. J., Luca, C. M. G. D., Ciullini, A., Dellarole, I. L., Fantin, A., et al. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.145303 · Cited by 1
Kilpeläinen, T. P., Yang, R., Toivio, J., Eteläinen, T. S., Lorenzo, F. D., Fastré, B., Zuo, C., Uhari-Väänänen, J. K., Julku, U. H., Cui, H., et al. (2025) · Experimental Neurology · doi:10.1016/j.expneurol.2025.115593 · Cited by 1
Stoll, A. C., & Harms, A. S. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1765195 · Cited by 1
“…studies demonstrate that exposure to pathological α -syn and PD-relevant genetic stressors induces mitochondrial dysfunction in astrocytes, including changes in mitochondrial morphology, bioenergetic stress, and impaired calcium–mitochondria coupling (Lindström et al., 2017; Wang et al., 2021).”
Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis
Datta, I., Raj, A., & Kaushal, A. (2022) · Springer eBooks · doi:10.1007/978-981-16-8313-8_10 · Cited by 2
Astroglial Iron Homeostasis and Neurodegenerative Diseases
Mukherjee, A. K., Dev, S., Ghosh, E., Asthana, S., & Mukhopadhyay, C. K. (2022) · Springer eBooks · doi:10.1007/978-981-16-8313-8_14 · Cited by 1
Doxycycline inhibits α-synuclein-associated pathologies in vitro and in vivoPreprint
Dominguez‐Meijide, A., Parrales, V., Vasili, E., González‐Lizárraga, F., König, A., Lázaro, D. F., Lannuzel, A., Haı̈k, S., Bel, E. D., Chehín, R. N., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.11.06.371229 · Cited by 1
GBA1 deficiency differentially affects endolysosomal trafficking in neurons versus astrocytesPreprint
Park, A. J., Fish, S., Samstag, C. L., Kim, M., Weiss, J., Yu, S., Callier, M. L., Chiu, E. H., Weiss, J., Hampe, C. S., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.12.697563 · Cited by 1
Martínez-Rodríguez, T. Y., & Buitrago, M. R. (2019) · Revista de la Facultad de Medicina · doi:10.15446/revfacmed.v67n3.69962
Les protéinopathies infectieuses de Parkinson et d’Alzheimer
Melki, R. (2020) · Bulletin de l Académie Nationale de Médecine · doi:10.1016/j.banm.2019.12.019
Sonninen, T.-M., Plotnikova, L. M., Laham-Karam, N., Goldsteins, G., Koıstınaho, J., & Lehtonen, Š. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-85764-2.00009-0
Experimental parkinsonism in modeling striatal astrocyte damage
Stavrovskaya, A. V., Воронков, Д. Н., Olshansky, A. S., Гущина, А. С., & Yamshchikova, N. G. (2019) · Annals of Clinical and Experimental Neurology · doi:10.25692/acen.2019.3.4
Astrocytes in multiple sclerosis
Piester, G., & Quintana, F. J. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-823848-6.00010-5
Mitochondrial Autophagy in Brain
Watzlawik, J. O., Hou, X., Fiesel, F. C., & Springer, W. (2024) · Springer eBooks · doi:10.1007/978-3-031-68237-7_9
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Валерьевна, К. О., Zvereva, M. I., & Olsufyeva, E. N. (2025) · Antibiot Khimioter = Antibiotics and Chemotherapy · doi:10.37489/0235-2990-2025-70-7-8-74-91
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Mothes, T., Portal, B., Konstantinidis, E., Eltom, K., Libard, S., Streubel-Gallasch, L., Ingelsson, M., Rostami, J., Lindskog, M., & Erlandsson, A. (2024) · Figshare · doi:10.6084/m9.figshare.26598035
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Self-citation
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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