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Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB

Tsui-Wen Chou, Nydia P Chang, Medha Krishnagiri, Aisha P Patel, View ORCID ProfileColm Atkins, View ORCID ProfileBrian P. Daniels
doi: https://doi.org/10.1101/2020.11.17.387175
Tsui-Wen Chou
1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA
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Nydia P Chang
1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA
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Medha Krishnagiri
1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA
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Aisha P Patel
1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA
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Colm Atkins
1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA
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Brian P. Daniels
1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA
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  • For correspondence: b.daniels@rutgers.edu
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Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by death of midbrain dopamine neurons. The pathogenesis of PD is poorly understood, though misfolded and/or aggregated forms of the protein α-synuclein have been implicated in several neurodegenerative disease processes, including neuroinflammation and astrocyte activation. Astrocytes in the midbrain play complex roles during PD, initiating both harmful and protective processes that vary over the course of disease. However, despite their significant regulatory roles during neurodegeneration, the cellular and molecular mechanisms that promote pathogenic astrocyte activity remain mysterious. Here, we show that α-synuclein preformed fibrils (PFFs) induce pathogenic activation of human midbrain astrocytes, marked by inflammatory transcriptional responses, downregulation of phagocytic function, and conferral of neurotoxic activity. These effects required the necroptotic kinases RIPK1 and RIPK3, but were independent of MLKL and necroptosis. Instead, both transcriptional and functional markers of astrocyte activation occurred via RIPK-dependent activation of NF-κB signaling. Our study identifies a previously unknown function for α-synuclein in promoting neurotoxic astrocyte activation, as well as new cell death-independent roles for RIP kinase signaling in the regulation of glial cell biology and neuroinflammation. Together, these findings highlight previously unappreciated molecular mechanisms of pathologic astrocyte activation and neuronal cell death with implications for Parkinsonian neurodegeneration.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 17, 2020.
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Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB
Tsui-Wen Chou, Nydia P Chang, Medha Krishnagiri, Aisha P Patel, Colm Atkins, Brian P. Daniels
bioRxiv 2020.11.17.387175; doi: https://doi.org/10.1101/2020.11.17.387175
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Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB
Tsui-Wen Chou, Nydia P Chang, Medha Krishnagiri, Aisha P Patel, Colm Atkins, Brian P. Daniels
bioRxiv 2020.11.17.387175; doi: https://doi.org/10.1101/2020.11.17.387175

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