Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the 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 the 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.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease [1]
We show that α-synuclein preformed fibrils (PFFs) induce robust inflammatory transcriptional signaling in human midbrain astrocytes, including transcripts associated with both the putative A1 and A2 astrocyte activation
Could be rescued via pharmacological blockade of receptorinteracting protein kinases-1 (RIPK1) and RIPK3 signaling, while mixed lineage kinase domain-like protein (MLKL) was dispensable for these effects, which occurred in the absence of astrocytic cell death
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease [1]. Previous work has described at least two putative subtypes of reactive astrocytes, termed “A1,” which are proinflammatory and neurotoxic, and “A2,” which are generally antiinflammatory and neurotrophic [18] These activation states have been distinguished by distinct transcriptional signatures and functional profiles, including the propensity to induce cell death in neurons (a marker of A1 astrocyte activity). Could be rescued via pharmacological blockade of RIPK1 and RIPK3 signaling, while MLKL was dispensable for these effects, which occurred in the absence of astrocytic cell death These data identify a previously unknown necroptosis-independent function for RIPK signaling in promoting a neurotoxic activation state in Caspase 3/7 activity assay Caspase 3/7 activity was measured using a chromogenic DEVD cleavage assay according to the manufacturer’s instructions (R&D Systems, Minneapolis, MN, #K106-100). Quantitative real-time PCR Total RNA from cultured cells was isolated with Qiagen RNeasy mini
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