α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Cav3.2 calcium signaling in astrocytes
Abstract 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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Translational Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40035-024-00401-4 |
| _version_ | 1797273472061145088 |
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| author | Emmanouela Leandrou Ioanna Chalatsa Dimitrios Anagnostou Christina Machalia Maria Semitekolou Vicky Filippa Manousos Makridakis Antonia Vlahou Ema Anastasiadou Kostas Vekrellis Evangelia Emmanouilidou |
| author_facet | Emmanouela Leandrou Ioanna Chalatsa Dimitrios Anagnostou Christina Machalia Maria Semitekolou Vicky Filippa Manousos Makridakis Antonia Vlahou Ema Anastasiadou Kostas Vekrellis Evangelia Emmanouilidou |
| author_sort | Emmanouela Leandrou |
| collection | DOAJ |
| description | Abstract 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 the α-synuclein conformers that activate microglia and/or astrocytes and the molecular pathways involved. Methods To investigate the role of α-synuclein conformers in the development and maintenance of neuroinflammation, we used primary quiescent microglia and astrocytes, post-mortem brain tissues from PD patients and A53T α-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 of α-synuclein oligomers in vivo and in vitro. Results We found that the presence of SDS-resistant hyper-phosphorylated α-synuclein oligomers, but not monomers, was correlated with sustained inflammatory responses, such as elevated levels of endogenous antibodies and cytokines and microglial activation. Similar oligomeric α-synuclein species were found in post-mortem human brain samples of PD patients but not control individuals. Detailed analysis revealed a decrease in Iba1Low/CD68Low 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 astrocytes of A53T mice. The sustained NF-κB activity triggered the upregulation of astrocytic T-type Cav3.2 Ca2+ channels, altering the astrocytic secretome and promoting the secretion of IGFBPL1, an IGF-1 binding protein with anti-inflammatory and neuroprotective potential. Conclusions Our work supports a causative link between the neuron-produced α-synuclein oligomers and sustained neuroinflammation in vivo and maps the signaling pathways that are stimulated in microglia and astrocytes. It also highlights the recruitment of astrocytic Cav3.2 channels as a potential neuroprotective mediator against the α-synuclein-induced neuroinflammation. Graphical Abstract |
| first_indexed | 2024-03-07T14:44:49Z |
| format | Article |
| id | doaj.art-82f7ab506cb94b4092be061937c6d2e5 |
| institution | Directory Open Access Journal |
| issn | 2047-9158 |
| language | English |
| last_indexed | 2024-03-07T14:44:49Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Translational Neurodegeneration |
| spelling | doaj.art-82f7ab506cb94b4092be061937c6d2e52024-03-05T20:05:24ZengBMCTranslational Neurodegeneration2047-91582024-02-0113112810.1186/s40035-024-00401-4α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Cav3.2 calcium signaling in astrocytesEmmanouela Leandrou0Ioanna Chalatsa1Dimitrios Anagnostou2Christina Machalia3Maria Semitekolou4Vicky Filippa5Manousos Makridakis6Antonia Vlahou7Ema Anastasiadou8Kostas Vekrellis9Evangelia Emmanouilidou10Department of Chemistry, School of Sciences, National and Kapodistrian University of AthensDepartment of Chemistry, School of Sciences, National and Kapodistrian University of AthensDepartment of Chemistry, School of Sciences, National and Kapodistrian University of AthensDepartment of Chemistry, School of Sciences, National and Kapodistrian University of AthensCenter for Basic Research, Biomedical Research Foundation of the Academy of AthensCenter for Basic Research, Biomedical Research Foundation of the Academy of AthensCenter for Systems Biology, Biomedical Research Foundation of the Academy of AthensCenter for Systems Biology, Biomedical Research Foundation of the Academy of AthensCenter for Basic Research, Biomedical Research Foundation of the Academy of AthensCenter for Basic Research, Biomedical Research Foundation of the Academy of AthensDepartment of Chemistry, School of Sciences, National and Kapodistrian University of AthensAbstract 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 the α-synuclein conformers that activate microglia and/or astrocytes and the molecular pathways involved. Methods To investigate the role of α-synuclein conformers in the development and maintenance of neuroinflammation, we used primary quiescent microglia and astrocytes, post-mortem brain tissues from PD patients and A53T α-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 of α-synuclein oligomers in vivo and in vitro. Results We found that the presence of SDS-resistant hyper-phosphorylated α-synuclein oligomers, but not monomers, was correlated with sustained inflammatory responses, such as elevated levels of endogenous antibodies and cytokines and microglial activation. Similar oligomeric α-synuclein species were found in post-mortem human brain samples of PD patients but not control individuals. Detailed analysis revealed a decrease in Iba1Low/CD68Low 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 astrocytes of A53T mice. The sustained NF-κB activity triggered the upregulation of astrocytic T-type Cav3.2 Ca2+ channels, altering the astrocytic secretome and promoting the secretion of IGFBPL1, an IGF-1 binding protein with anti-inflammatory and neuroprotective potential. Conclusions Our work supports a causative link between the neuron-produced α-synuclein oligomers and sustained neuroinflammation in vivo and maps the signaling pathways that are stimulated in microglia and astrocytes. It also highlights the recruitment of astrocytic Cav3.2 channels as a potential neuroprotective mediator against the α-synuclein-induced neuroinflammation. Graphical Abstracthttps://doi.org/10.1186/s40035-024-00401-4α-SynucleinOligomersNeuroinflammationp38MAPK signalingAstrocytesCav3.2 calcium channel |
| spellingShingle | Emmanouela Leandrou Ioanna Chalatsa Dimitrios Anagnostou Christina Machalia Maria Semitekolou Vicky Filippa Manousos Makridakis Antonia Vlahou Ema Anastasiadou Kostas Vekrellis Evangelia Emmanouilidou α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Cav3.2 calcium signaling in astrocytes Translational Neurodegeneration α-Synuclein Oligomers Neuroinflammation p38MAPK signaling Astrocytes Cav3.2 calcium channel |
| title | α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Cav3.2 calcium signaling in astrocytes |
| title_full | α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Cav3.2 calcium signaling in astrocytes |
| title_fullStr | α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Cav3.2 calcium signaling in astrocytes |
| title_full_unstemmed | α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Cav3.2 calcium signaling in astrocytes |
| title_short | α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Cav3.2 calcium signaling in astrocytes |
| title_sort | α synuclein oligomers potentiate neuroinflammatory nf κb activity and induce cav3 2 calcium signaling in astrocytes |
| topic | α-Synuclein Oligomers Neuroinflammation p38MAPK signaling Astrocytes Cav3.2 calcium channel |
| url | https://doi.org/10.1186/s40035-024-00401-4 |
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