α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Ca_(v)3.2 calcium signaling in astrocytes  

作　　者：Emmanouela Leandrou Ioanna Chalatsa Dimitrios Anagnostou Christina Machalia Maria Semitekolou Vicky Filippa Manousos Makridakis Antonia Vlahou Ema Anastasiadou Kostas Vekrellis Evangelia Emmanouilidou 

机构地区：[1]Department of Chemistry,School of Sciences,National and Kapodistrian University of Athens,Panepistimioupolis Zografou,15772 Athens,Greece [2]Center for Basic Research,Biomedical Research Foundation of the Academy of Athens,Soranou Efesiou 4,11527 Athens,Greece [3]Center for Systems Biology,Biomedical Research Foundation of the Academy of Athens,Soranou Efesiou 4,11527 Athens,Greece [4]Present Address:School of Medicine,University of Crete,71003 Heraklion,Greece

出　　处：《Translational Neurodegeneration》2024年第1期921-948,共28页转化神经变性病(英文)

基　　金：funded by a Michael J.Fox Foundation grant,Target Advancement Program 2018 and a Hellenic Foundation for Research and Innovation(HFRI)Grant(581)to EE.Partial financial support was received from Special Account for Research Grants of NKUA(18638)to EE and a PhD scholarship grant to D.A.(2022-050-0502-52576)from the Greek State Scholarships Foundation(I.K.Y.)through the action“Scholarships Programs for post-graduate studies”in the framework of the Operational Program“Human Resources Development Program,Education and Lifelong Learning”of the National Strategic Reference Framework(NSRF 2014–2020).

摘　　要：Background It is now realized that Parkinson’s disease(PD)pathology extends beyond the substantia nigra,affecting both central and peripheral nervous systems,and exhibits a variety of non-motor symptoms often preceding motor features.Neuroinflammation induced by activated microglia and astrocytes is thought to underlie these manifestations.α-Synuclein aggregation has been linked with sustained neuroinflammation in PD,aggravating neuronal degeneration;however,there is still a lack of critical information about the structural identity of theα-synuclein conformers that activate microglia and/or astrocytes and the molecular pathways involved.Methods To investigate the role ofα-synuclein conformers in the development and maintenance of neuroinflammation,we used primary quiescent microglia and astrocytes,post-mortem brain tissues from PD patients and A53Tα-synuclein transgenic mice that recapitulate key features of PD-related inflammatory responses in the absence of cell death,i.e.,increased levels of pro-inflammatory cytokines and complement proteins.Biochemical and-omics techniques including RNAseq and secretomic analyses,combined with 3D reconstruction of individual astrocytes and live calcium imaging,were used to uncover the molecular mechanisms underlying glial responses in the presence ofα-synuclein oligomers in vivo and in vitro.Results We found that the presence of SDS-resistant hyper-phosphorylatedα-synuclein oligomers,but not monomers,was correlated with sustained inflammatory responses,such as elevated levels of endogenous antibodies and cytokines and microglial activation.Similar oligomericα-synuclein species were found in post-mortem human brain samples of PD patients but not control individuals.Detailed analysis revealed a decrease in Iba1^(Low)/CD68^(Low) microglia and robust alterations in astrocyte number and morphology including process retraction.Our data indicated an activation of the p38/ATF2 signaling pathway mostly in microglia and a sustained induction of the NF-κB pathway in astrocyte

关 键 词：Α-SYNUCLEIN OLIGOMERS Neuroinflammation p38^(MAPK)signaling ASTROCYTES Ca_(v)3.2 calcium channel NF-ΚB IGFBPL1 

分 类 号：R741[医药卫生—神经病学与精神病学]