Pericytes take up and degrade α-synuclein but succumb to apoptosis under cellular stress
© 2022. The Author(s)..
Parkinson's disease (PD) is characterised by the progressive loss of midbrain dopaminergic neurons and the presence of aggregated α-synuclein (α-syn). Pericytes and microglia, two non-neuronal cells contain α-syn in the human brain, however, their role in disease processes is poorly understood. Pericytes, found surrounding the capillaries in the brain are important for maintaining the blood-brain barrier, controlling blood flow and mediating inflammation. In this study, primary human brain pericytes and microglia were exposed to two different α-synuclein aggregates. Inflammatory responses were assessed using immunocytochemistry, cytometric bead arrays and proteome profiler cytokine array kits. Fixed flow cytometry was used to investigate the uptake and subsequent degradation of α-syn in pericytes. We found that the two α-syn aggregates are devoid of inflammatory and cytotoxic actions on human brain derived pericytes and microglia. Although α-syn did not induce an inflammatory response, pericytes efficiently take up and degrade α-syn through the lysosomal pathway but not the ubiquitin-proteasome system. Furthermore, when pericytes were exposed the ubiquitin proteasome inhibitor-MG132 and α-syn aggregates, there was profound cytotoxicity through the production of reactive oxygen species resulting in apoptosis. These results suggest that the observed accumulation of α-syn in pericytes in human PD brains likely plays a role in PD pathogenesis, perhaps by causing cerebrovascular instability, under conditions of cellular stress.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Scientific reports - 12(2022), 1 vom: 15. Okt., Seite 17314 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Stevenson, Taylor J [VerfasserIn] |
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| Links: |
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| Themen: |
Alpha-Synuclein |
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| Anmerkungen: |
Date Completed 18.10.2022 Date Revised 09.01.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41598-022-20261-0 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM347587119 |
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| 245 | 1 | 0 | |a Pericytes take up and degrade α-synuclein but succumb to apoptosis under cellular stress |
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| 520 | |a © 2022. The Author(s). | ||
| 520 | |a Parkinson's disease (PD) is characterised by the progressive loss of midbrain dopaminergic neurons and the presence of aggregated α-synuclein (α-syn). Pericytes and microglia, two non-neuronal cells contain α-syn in the human brain, however, their role in disease processes is poorly understood. Pericytes, found surrounding the capillaries in the brain are important for maintaining the blood-brain barrier, controlling blood flow and mediating inflammation. In this study, primary human brain pericytes and microglia were exposed to two different α-synuclein aggregates. Inflammatory responses were assessed using immunocytochemistry, cytometric bead arrays and proteome profiler cytokine array kits. Fixed flow cytometry was used to investigate the uptake and subsequent degradation of α-syn in pericytes. We found that the two α-syn aggregates are devoid of inflammatory and cytotoxic actions on human brain derived pericytes and microglia. Although α-syn did not induce an inflammatory response, pericytes efficiently take up and degrade α-syn through the lysosomal pathway but not the ubiquitin-proteasome system. Furthermore, when pericytes were exposed the ubiquitin proteasome inhibitor-MG132 and α-syn aggregates, there was profound cytotoxicity through the production of reactive oxygen species resulting in apoptosis. These results suggest that the observed accumulation of α-syn in pericytes in human PD brains likely plays a role in PD pathogenesis, perhaps by causing cerebrovascular instability, under conditions of cellular stress | ||
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| 700 | 1 | |a Johnson, Rebecca H |e verfasserin |4 aut | |
| 700 | 1 | |a Savistchenko, Jimmy |e verfasserin |4 aut | |
| 700 | 1 | |a Rustenhoven, Justin |e verfasserin |4 aut | |
| 700 | 1 | |a Woolf, Zoe |e verfasserin |4 aut | |
| 700 | 1 | |a Smyth, Leon C D |e verfasserin |4 aut | |
| 700 | 1 | |a Murray, Helen C |e verfasserin |4 aut | |
| 700 | 1 | |a Faull, Richard L M |e verfasserin |4 aut | |
| 700 | 1 | |a Correia, Jason |e verfasserin |4 aut | |
| 700 | 1 | |a Schweder, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Heppner, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Turner, Clinton |e verfasserin |4 aut | |
| 700 | 1 | |a Melki, Ronald |e verfasserin |4 aut | |
| 700 | 1 | |a Dieriks, Birger V |e verfasserin |4 aut | |
| 700 | 1 | |a Curtis, Maurice A |e verfasserin |4 aut | |
| 700 | 1 | |a Dragunow, Michael |e verfasserin |4 aut | |
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