Pericytes take up and degrade α-synuclein but succumb to apoptosis under cellular stress.

Autor: Stevenson TJ; Department of Pharmacology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand., Johnson RH; Department of Pharmacology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand., Savistchenko J; Alternative Energies and Atomic Energy Commission and Laboratory of Neurodegenerative Diseases, Molecular Imaging Research Center, Francois Jacob Institute, National Center for Scientific Research, Fontenay-Aux-Roses, France., Rustenhoven J; Department of Pharmacology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand., Woolf Z; Department of Pharmacology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand., Smyth LCD; Department of Pharmacology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand., Murray HC; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand.; Department of Anatomy and Medical Imaging, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand., Faull RLM; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand.; Department of Anatomy and Medical Imaging, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand., Correia J; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand.; Auckland City Hospital, 2 Park Road, Auckland, 1010, New Zealand., Schweder P; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand.; Auckland City Hospital, 2 Park Road, Auckland, 1010, New Zealand., Heppner P; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand.; Starship Children's Hospital, 2 Park Road, Auckland, 1010, New Zealand., Turner C; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand.; Department of Anatomical Pathology, Lab Plus, Auckland City Hospital, 2 Park Road, Auckland, New Zealand., Melki R; Alternative Energies and Atomic Energy Commission and Laboratory of Neurodegenerative Diseases, Molecular Imaging Research Center, Francois Jacob Institute, National Center for Scientific Research, Fontenay-Aux-Roses, France., Dieriks BV; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand.; Department of Anatomy and Medical Imaging, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand., Curtis MA; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand. m.curtis@auckland.ac.nz.; Department of Anatomy and Medical Imaging, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. m.curtis@auckland.ac.nz., Dragunow M; Department of Pharmacology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. m.dragunow@auckland.ac.nz.; Centre for Brain Research, University of Auckland, Private Bag 920139, Auckland, 1142, New Zealand. m.dragunow@auckland.ac.nz.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Oct 15; Vol. 12 (1), pp. 17314. Date of Electronic Publication: 2022 Oct 15.
DOI: 10.1038/s41598-022-20261-0
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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