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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]
In the citing paper
“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]
Citations
Cites
Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997) · Nature · doi:10.1038/42166 · Cited by 8,382
In vivo demonstration that α-synuclein oligomers are toxic
Winner, B., Jappelli, R., Maji, S. K., Desplats, P. A., Boyer, L., Aigner, S., Hetzer, C., Loher, T., Vilar, M., Campioni, S., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1100976108 · Cited by 1,463
Johe, K. K., Hazel, T. G., Müller, T. H., Dugich‐Djordjevic, M. M., & McKay, R. D. G. (1996) · Genes & Development · doi:10.1101/gad.10.24.3129 · Cited by 1,154
Devi, L., Raghavendran, V., Prabhu, B. M., Avadhani, N. G., & Anandatheerthavarada, H. K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710012200 · Cited by 1,127
Middeldorp, J., & Hol, E. M. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.01.005 · Cited by 1,080
Lee, H.-J., Suk, J.-E., Patrick, C., Bae, E.-J., Cho, J.-H., Rho, S., Hwang, D., Masliah, E., & Lee, S.-J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.081125 · Cited by 877
Hansen, C., Angot, E., Bergström, A.-L., Steiner, J. A., Pieri, L., Paul, G., Outeiro, T. F., Melki, R., Kallunki, P., Fog, K., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43366 · Cited by 842
The lysosome: from waste bag to potential therapeutic target
Appelqvist, H., Wäster, P., Kågedal, K., & Öllinger, K. (2013) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjt022 · Cited by 772
Different Species of α-Synuclein Oligomers Induce Calcium Influx and Seeding
Danzer, K. M., Haasen, D., Karow, A. R., Moussaud, S., Habeck, M., Giese, A., Kretzschmar, H., Hengerer, B., & Kostka, M. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2617-07.2007 · Cited by 765
Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia
Fellner, L., Irschick, R., Schanda, K., Reindl, M., Klimaschewski, L., Poewe, W., Wenning, G. K., & Stefanova, N. (2013) · Glia · doi:10.1002/glia.22437 · Cited by 697
Research works printed but not linked: 1
- Lööv, 2012, Engulfing astrocytes protect neurons from contact-induced apoptosis following injury, PLoS One, 7, 10.1371/journal.pone.0033090 · DOI
Cited by
Sorted by citations
Neuroinflammation in the central nervous system: Symphony of glial cells
Yang, Q., & Zhou, J. (2018) · Glia · doi:10.1002/glia.23571 · Cited by 539
“The aggregated proteins in glial cells cause detrimental cellular processes, such as mitochondrial abnormalities, and disrupt basic intracellular protein degradation systems (Fellner, Jellinger, Wenning, & Stefanova, 2011; Lindstrom et al., 2017).”
BackgroundNew insights into the complex role of mitochondria in Parkinson’s disease
Grünewald, A., Kumar, K. R., & Sue, C. M. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.09.003 · Cited by 375
“In a recent series of publications by the Erlandsson lab, uptake, degradation and toxicity of oligomeric alpha-synuclein were tested in a co-culture system of mouse primary neurons, astrocytes and oligodendrocytes (Lindstrom et al., 2017).”
BackgroundAlpha-synuclein oligomers: a new hope
Bengoa‐Vergniory, N., Roberts, R. F., Wade‐Martins, R., & Alegre‐Abarrategui, J. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1755-1 · Cited by 349
Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes
Rostami, J., Holmqvist, S., Lindström, V., Sigvardson, J., Westermark, G. T., Ingelsson, M., Bergström, J., Roybon, L., & Erlandsson, A. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.0983-17.2017 · Cited by 339
“This concentration was chosen based on our previous investigations of neuronal– glial cocultures, demonstrating that astrocytes rapidly internalized particularly large amounts of -SYN oligomers (Lindström et al., 2017).”
MethodSelf-citationSengupta, U., & Kayed, R. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102270 · Cited by 318
“PSP, PD, DLB and ALS, where microglia and astrocytes play important roles in neuroinflammation (Alster et al., 2020; Amin et al., 2020; Bachiller et al., 2018; GuzmanMartinez et al., 2019; Lindstrom et al., 2017).”
BackgroundMitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases
Cai, Q., & Jeong, Y. Y. (2020) · Cells · doi:10.3390/cells9010150 · Cited by 270
The Role of α-Synuclein Oligomers in Parkinson’s Disease
Du, X.-Y., Xie, X.-X., & Liu, R.-T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228645 · Cited by 234
“However, the long-term storage of α-syn oligomers in astrocytes can affect their mitochondrial integrity and make for neurotoxicity [34].”
BackgroundRostami, J., Mothes, T., Kolahdouzan, M., Eriksson, O., Moslem, M., Bergström, J., Ingelsson, M., O’Callaghan, P., Healy, L. M., Falk, A., et al. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02158-3 · Cited by 224
“We have previously shown that astrocytes accumulate large amounts of αSYN and Aβ aggregates, resulting in severe cellular stress [11, 12, 23, 24].”
BackgroundMethodSelf-citationRösler, T. W., Marvian, A. T., Brendel, M., Nykänen, N.-P., Höllerhage, M., Schwarz, S. C., Hopfner, F., Koeglsperger, T., Respondek, G., Schweyer, K., et al. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.101644 · Cited by 231
Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189
Sorrentino, Z. A., Giasson, B. I., & Chakrabarty, P. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-01977-2 · Cited by 179
The concept of alpha-synuclein as a prion-like protein: ten years after
Steiner, J. A., Quansah, E., & Brundin, P. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2814-1 · Cited by 183
“associated toxic cellular effects (Lindström et al. 2017).”
Rastogi, S., Sharma, V., Bharti, P. S., Rani, K., Modi, G. P., Nikolajeff, F. K., & Kumar, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22010440 · Cited by 176
Glial phagocytic clearance in Parkinson’s disease
Tremblay, M.-E., Cookson, M. R., & Civiero, L. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0314-8 · Cited by 152
“The accumulation of aggregated α-syn in astrocytes also disrupts their lysosomes, impacts mitochondria homeostasis and may induce cell-to-cell transfer of α-syn via tunneling nanotubes [23, 25, 26].”
BackgroundThe immune system in Parkinson's disease: what we know so far
Roodveldt, C., Bernardino, L. I., Çakmak, Ö. Ö., Dragić, M., Fladmark, K. E., Ertan, S., Aktaş, B., Pita, C., Ciglar, L., Garraux, G., et al. (2024) · Brain · doi:10.1093/brain/awae177 · Cited by 151
“104,107,132,163 Studies in vitro and in vivo have demonstrated that rotenone aggra-vates NLRP3 pro-inflammatory signalling and dopaminergic neuronal loss via mitochondrial damage in microglia.”
BackgroundKovács, G. G., Xie, S. X., Robinson, J. L., Lee, E. B., Smith, D. H., Schuck, T., Lee, V. M. ‐., & Trojanowski, J. Q. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0552-y · Cited by 137
“Astrocytes do have phagocytic receptors and have been show to internalize or engulf pathological alpha-synuclein and most likely play a role in clearance and their degradation [12, 30, 39, 42, 46].”
BackgroundBriston, T., & Hicks, A. R. (2018) · Biochemical Society Transactions · doi:10.1042/bst20180025 · Cited by 131
Peelaerts, W., Bousset, L., Baekelandt, V., & Melki, R. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2839-5 · Cited by 128
Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective
Mulica, P., Grünewald, A., & Pereira, S. L. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.668517 · Cited by 126
Reactive microglia enhance the transmission of exosomal α-synuclein via toll-like receptor 2
Xia, Y., Zhang, G., Kou, L., Yin, S., Han, C., Hu, J., Wan, F., Sun, Y., Wu, J., Li, Y., et al. (2021) · Brain · doi:10.1093/brain/awab122 · Cited by 123
Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies
Cascella, R., Bigi, A., Cremades, N., & Cecchi, C. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04166-9 · Cited by 130
“Overall, different studies on the toxic effect of αSyn oligomers suggest that there are multiple mechanisms by which these species can induce mitochondrial dysfunction both in neurons and astrocytes [74, 75].”
BackgroundParkinson’s Disease–Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance
Streubel-Gallasch, L., Giusti, V., Sandre, M., Tessari, I., Plotegher, N., Giusto, E., Masato, A., Iovino, L., Battisti, I., Arrigoni, G., et al. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02327-8 · Cited by 100
Self-citationContribution of astrocytes to neuropathology of neurodegenerative diseases
Acıoğlu, Ç., Li, L., & Elkabes, S. (2021) · Brain Research · doi:10.1016/j.brainres.2021.147291 · Cited by 119
New Perspectives on Roles of Alpha-Synuclein in Parkinson’s Disease
Zhang, G., Xia, Y. F., Wan, F. J., Ma, K., Guo, X., Kou, L., Yin, S., Han, C., Liu, L., Huang, J., et al. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00370 · Cited by 116
“Astrocytes are able to take up and degrade α-syn oligomers via the lysosomal pathway (Lindstrom et al., 2017).”
BackgroundLysosome and Inflammatory Defects in GBA1‐Mutant Astrocytes Are Normalized by LRRK2 Inhibition
Sanyal, A., DeAndrade, M. P., Novis, H. S., Lin, S. C., Chang, J., Lengacher, N. A., Tomlinson, J. J., Tansey, M. G., & LaVoie, M. J. (2020) · Movement Disorders · doi:10.1002/mds.27994 · Cited by 111
Astrocyte and Alzheimer’s disease
Cai, Z., Wan, C., & Liu, Z. (2017) · Journal of Neurology · doi:10.1007/s00415-017-8593-x · Cited by 115
“Furthermore, a focus on the research of cognitive impairment and dementia, which are related to astrocytic pathogenesis, has also been established, including Alzheimer’s disease [18–20], Parkinson disease dementia [21], vascular cognitive impairment or dementia [22, 23], frontotemporal dementia [15, 24], dementia with…”
BackgroundInnate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases
Novellino, F., Saccà, V., Donato, A., Zaffino, P., Spadea, M. F., Vismara, M. F. M., Arcidiacono, B., Malara, N., Presta, I., & Donato, G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031115 · Cited by 107
“In vitro studies have demonstrated that astrocytes are able to phagocytize fibrillar α-synuclein [91,92], however they tend to accumulate α-synuclein in intracellular agglomerates rather than degrade it.”
BackgroundThe A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration
Hinkle, J. T., Dawson, V. L., & Dawson, T. M. (2019) · Movement Disorders · doi:10.1002/mds.27718 · Cited by 100
Immune responses in the Parkinson's disease brain
Weiss, F. C., Labrador‐Garrido, A., Dzamko, N. L., & Halliday, G. M. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105700 · Cited by 100
Estes, R., Lin, B. C., Khera, A., & Davis, M. Y. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.788695 · Cited by 99
Import and Export of Misfolded α-Synuclein
Rodriguez, L., Marano, M. M., & Tandon, A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00344 · Cited by 93
Targeted attenuation of elevated histone marks at SNCA alleviates α‐synuclein in Parkinson's disease
Guhathakurta, S., Kim, J.-I., Adams, L., Basu, S., Song, M. K., Adler, E. R., Je, G., Fiadeiro, M. B., & Kim, Y. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202012188 · Cited by 95
“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
Kovács, G. G., Lee, V. M., & Trojanowski, J. Q. (2017) · Brain Pathology · doi:10.1111/bpa.12536 · Cited by 93
Astrocytes autophagy in aging and neurodegenerative disorders
Wang, J., & Xu, C. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109691 · Cited by 88
Altay, M. F., Liu, A. K. L., Holton, J. L., Parkkinen, L., & Lashuel, H. A. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01468-8 · Cited by 85
“…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.”
BackgroundInfluentialWang, C., Yang, T., Liang, M., Xie, J., & Song, N. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00265-y · Cited by 90
Chavarría, C., Rodríguez-Bottero, S., Quijano, C., Cassina, P., & Souza, J. M. (2018) · Biochemical Journal · doi:10.1042/bcj20180297 · Cited by 83
Interactions of α-synuclein oligomers with lipid membranes
Musteikytė, G., Jayaram, A. K., Xu, C. K., Vendruscolo, M., Krainer, G., & Knowles, T. P. J. (2020) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2020.183536 · Cited by 83
Doxycycline Inhibits α-Synuclein-Associated Pathologies in Vitro and in Vivo
Dominguez-Meijide, A., Parrales, V., Vasili, E., González-Lizárraga, F., König, A., Lázaro, D. F., Lannuzel, A., Haik, S., Del Bel, E., Chehín, R., et al. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105256 · Cited by 81
Xu, H., Wang, Y., Song, N., Wang, J., Jiang, H. F., & Xie, J. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00455 · Cited by 82
“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
Cardinale, A., Calabrese, V., de Iure, A., & Picconi, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126517 · Cited by 79
Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease
Olsen, M., Aguilar, X., Sehlin, D., Fang, X. T., Antoni, G., Erlandsson, A., & Syvänen, S. (2018) · Molecular Imaging and Biology · doi:10.1007/s11307-017-1153-z · Cited by 80
Self-citationMechanisms of alpha-synuclein toxicity: An update and outlook
Brás, I. C., Xylaki, M., & Outeiro, T. F. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.10.005 · Cited by 78
Autophagy in Astrocytes and its Implications in Neurodegeneration
Sung, K., & Jiménez-Sánchez, M. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.12.041 · Cited by 78
Wiseman, J. A., Murray, H. C., Faull, R. L. M., Dragunow, M., Turner, C. P., Dieriks, B. V., & Curtis, M. A. (2024) · npj Parkinson s Disease · doi:10.1038/s41531-023-00614-w · Cited by 73
“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 .”
BackgroundInfluentialAntibodies against alpha‐synuclein: tools and therapies
Vaikath, N. N., Hmila, I., Gupta, V. R., Erskine, D., Ingelsson, M., & El‐Agnaf, O. M. A. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14713 · Cited by 75
Self-citationNeuroinflammation and Glial Phenotypic Changes in Alpha-Synucleinopathies
Refolo, V., & Stefanova, N. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00263 · Cited by 72
“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).”
BackgroundBeretta, C., Nikitidou, E., Streubel-Gallasch, L., Ingelsson, M., Sehlin, D., & Erlandsson, A. (2020) · Scientific Reports · doi:10.1038/s41598-020-72355-2 · Cited by 71
Self-citationRegulation of neuronal autophagy and the implications in neurodegenerative diseases
Cai, Q., & Ganesan, D. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105582 · Cited by 70
Suppression of astrocytic autophagy by αB-crystallin contributes to α-synuclein inclusion formation
Lu, S., Guo, Y.-S., Liang, P., Zhang, S., Yin, S., Yin, Y., Wang, X., Ding, F., Gu, X., & Zhou, J. (2019) · Translational Neurodegeneration · doi:10.1186/s40035-018-0143-7 · Cited by 74
“For instance, the accumulation of α-synuclein induces astrocytic mitochondrial impairments [4].”
InfluentialAlpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease
Saramowicz, K., Siwecka, N., Galita, G., Kucharska-Lusina, A., Rozpędek‐Kamińska, W., & Majsterek, I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010360 · Cited by 79
“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].”
BackgroundSchaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01026-0 · Cited by 63
“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].”
BackgroundSerratos, I. N., Hernández‐Pérez, E., Campos, C., Aschner, M., & Santamarı́a, A. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02596-3 · Cited by 70
Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson’s disease
Yang, Y., Song, J., Choi, Y. R., Kim, S. H., Seok, M., Wulansari, N., Darsono, W. H. W., Kwon, O., Chang, M., Park, S. M., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2110746119 · Cited by 61
Díaz, E. F., Labra, V. C., Alvear, T. F., Mellado, L. A., Inostroza, C. A., Oyarzún, J. E., Salgado, N., Quintanilla, R. A., & Orellana, J. A. (2019) · Glia · doi:10.1002/glia.23631 · Cited by 63
“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).”
BackgroundInfluentialHerman, S., Djaldetti, R., Mollenhauer, B., & Offen, D. (2023) · Brain · doi:10.1093/brain/awac261 · Cited by 62
Ferrer, I. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.07.004 · Cited by 65
The Dawn of Mitophagy: What Do We Know by Now?
Belousov, D. M., Вячеславовна, М. Е., Somasundaram, S. G., Kirkland, C. E., & Aliev, G. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200522202319 · Cited by 60
“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
Wu, J., Wu, J., Chen, T., Cai, J., & Ren, R. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105880 · Cited by 62
“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 61
Filippini, A., Gennarelli, M., & Russo, I. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00649-9 · Cited by 61
Glial mitochondrial function and dysfunction in health and neurodegeneration
McAvoy, K., & Kawamata, H. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2019.103417 · Cited by 59
Intermediates of α-synuclein aggregation: Implications in Parkinson's disease pathogenesis
Gadhe, L. G., Sakunthala, A., Mukherjee, S., Gahlot, N., Bera, R., Sawner, A. S., Kadu, P., & Maji, S. K. (2021) · Biophysical Chemistry · doi:10.1016/j.bpc.2021.106736 · Cited by 56
Huang, J. A., Ding, J., Wang, X., Gu, C., He, Y., Li, Y., Fan, H., Xie, Q., Qi, X., Wang, Z., et al. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.09.002 · Cited by 59
Bigi, A., Cascella, R., Chiti, F., & Cecchi, C. (2022) · BioEssays · doi:10.1002/bies.202200086 · Cited by 56
“evoked mitochondrial abnormalities leading to cellular degeneration and death.[46,47] More recently, oligomeric αSwas reported to interact”
BackgroundThe role of glial autophagy in Alzheimer’s disease
Litwiniuk, A., Juszczak, G. R., Stankiewicz, A. M., & Urbańska, K. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02242-5 · Cited by 54
Neurodegeneration cell per cell
Balusu, S., Praschberger, R., Lauwers, E., Strooper, B. D., & Verstreken, P. (2023) · Neuron · doi:10.1016/j.neuron.2023.01.016 · Cited by 53
“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
Giusti, V., Kaur, G., Giusto, E., & Civiero, L. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00703-1 · Cited by 54
“This impairs the astrocytes’ capability to support neuronal metabo - lism and synaptic function [102, 140].”
BackgroundCalderón‐Garcidueñas, L., Reynoso-Robles, R., Pérez-Guillé, B., Mukherjee, P. S., & González-Maciel, A. (2017) · Environmental Research · doi:10.1016/j.envres.2017.08.008 · Cited by 51
Shamoto‐Nagai, M., Hisaka, S., Naoi, M., & Maruyama, W. (2018) · Journal of Clinical Biochemistry and Nutrition · doi:10.3164/jcbn.18-25 · Cited by 53
Neurons and Glia Interplay in α-Synucleinopathies
Mavroeidi, P., & Xilouri, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094994 · Cited by 55
“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 52
“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
Wang, R., Ren, H., Kaznacheyeva, E. V., Lu, X., & Wang, G. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00957-z · Cited by 51
Ginseng gintonin, aging societies, and geriatric brain diseases
Choi, S.-H., Lee, R., Nam, S. M., Kim, D.-G., Cho, I., Kim, H., Cho, Y., Rhim, H., & Nah, S.-Y. (2020) · Integrative Medicine Research · doi:10.1016/j.imr.2020.100450 · Cited by 51
Extracellular clusterin limits the uptake of α‐synuclein fibrils by murine and human astrocytes
Filippini, A., Mutti, V., Faustini, G., Longhena, F., Ramazzina, I., Rizzi, F., Kaganovich, A., Roosen, D. A., Landeck, N., Duffy, M. F., et al. (2020) · Glia · doi:10.1002/glia.23920 · Cited by 49
“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).”
BackgroundGustafsson, G., Lindström, V., Rostami, J., Nordström, E. K. L., Lannfelt, L., Bergström, J. J. E., Ingelsson, M., & Erlandsson, A. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-1018-z · Cited by 48
“Due to incomplete digestion, intracellular α-syn deposits remained in the astrocytes, which resulted in a mitochondrial impairment [25].”
BackgroundMethodResultInfluentialSelf-citationThe unlikely partnership between LRRK 2 and α‐synuclein in Parkinson's disease
Cresto, N., Gardier, C., Gubinelli, F., Gaillard, M., Liot, G., West Andrew, B., & Brouillet, E. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.14182 · Cited by 49
Natale, F., Fusco, S., & Grassi, C. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00326-w · Cited by 49
“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].”
BackgroundMeng, Y., Ding, J., Li, C., Fan, H., He, Y., & Qiu, P. (2020) · Toxicology Letters · doi:10.1016/j.toxlet.2020.06.016 · Cited by 47
Alpha-synuclein and the prion hypothesis in Parkinson's disease
Melki, R. (2018) · Revue Neurologique · doi:10.1016/j.neurol.2018.08.002 · Cited by 52
Astrocytic uptake of neuronal corpses promotes cell‐to‐cell spreading of tau pathology
Mothes, T., Portal, B., Konstantinidis, E., Eltom, K., Libard, S., Streubel-Gallasch, L., Ingelsson, M., Rostami, J., Lindskog, M., & Erlandsson, A. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01589-8 · Cited by 43
“This intracellular storage of pathological proteins results in severe cellular stress, indicated by lysosomal and mitochondrial deficiencies [11-16].”
BackgroundSelf-citationAstrocytes in Parkinson’s Disease: From Role to Possible Intervention
Wang, T., Sun, Y., & Dettmer, U. (2023) · Cells · doi:10.3390/cells12192336 · Cited by 48
Norwitz, N. G., Soto-Mota, A., Norwitz, S. G., & Clarke, K. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00184 · Cited by 42
“…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…”
BackgroundYang, N., Li, Z., Han, D., Mi, X., Tian, M., Liu, T., Li, Y., He, J., Kuang, C., Cao, Y., et al. (2020) · Aging · doi:10.18632/aging.103074 · Cited by 43
“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].”
BackgroundDiniz, L. P., Matias, I. C. P., Araújo, A. P. B., Garcia, M. N., Barros‐Aragão, F. G. Q., Alves‐Leon, S. V., de Souza, J. M., Foguel, D., Figueiredo, C. P., Braga, C. A. D. C. D. A., et al. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14710 · Cited by 45
“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?
Morgan, A. H., Rees, D. J., Andrews, Z. B., & Davies, J. S. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.12.027 · Cited by 40
Lysosomal Functions in Glia Associated with Neurodegeneration
Kreher, C., Favret, J., Maulik, M., & Shin, D. (2021) · Biomolecules · doi:10.3390/biom11030400 · Cited by 38
“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 39
“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
Domingues, R., Sant’Anna, R., da Fonseca, A. C. C., Robbs, B. K., Foguel, D., & Outeiro, T. F. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105696 · Cited by 38
A secret that underlies Parkinson's disease: The damaging cycle
Sun, F., Deng, Y., Han, X., Liu, Q., Zhang, P., Manzoor, R., & Ma, H. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2019.104484 · Cited by 37
Glial cells in Parkinson´s disease: protective or deleterious?
Domingues, A. V., Pereira, I. M., Vilaça-Faria, H., Salgado, A. J., Rodrigues, A. J., & Teixeira, F. G. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03584-x · Cited by 38
“Simplistically, there may exist a threshold that further affects mitochondrial integrity in astrocytes and then leads to neurotoxicity [215].”
BackgroundEndosomal-Lysosomal Processing of Neurodegeneration-Associated Proteins in Astrocytes
Wong, C.-O. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21145149 · Cited by 31
Jacquet, A. D. R., Denis, H. L., Cicchetti, F., & Alpaugh, M. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-00999-7 · Cited by 36
Khor, S. L. Q., Ng, K. Y., Koh, R. Y., & Chye, S. M. (2023) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527322666230330093829 · Cited by 37
Huntington, T. E., & Srinivasan, R. (2021) · Aging and disease · doi:10.14336/ad.2021.0517 · Cited by 34
“patients [3, 161, 164] and in human derived astrocyte cultures [104, 162, 165-167].”
BackgroundCheney, L., Guzik, H. M., Macaluso, F., Macián, F., Cuervo, A. M., & Berman, J. W. (2020) · Cells · doi:10.3390/cells9061426 · Cited by 34
Yahi, N., Scala, C. D., Chahinian, H., & Fantini, J. (2021) · Glycoconjugate Journal · doi:10.1007/s10719-021-10012-0 · Cited by 33
The role of glia in Parkinson's disease: Emerging concepts and therapeutic applications
Kuter, K. Z., Cenci, M. A., & Carta, A. R. (2020) · Progress in brain research · doi:10.1016/bs.pbr.2020.02.004 · Cited by 31
Xiang, L., Wang, Y., Liu, S., Liu, B., Jin, X., & Cao, X. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411275 · Cited by 32
The Role of Glial Mitochondria in α-Synuclein Toxicity
Jeon, Y., Kwon, Y., Jo, M., Lee, S., Kim, S., & Kim, H. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.548283 · Cited by 31
“Lindstrom et al. (2017) tried to elucidate the clearance mechanism of toxic α-syn in glial cells.”
BackgroundInfluential
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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