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

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 alpha-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 alpha-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-kappa B signaling. Our study identifies a previously unknown function for alpha-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.

Automated summary

This study reveals that preformed fibrils of alpha-synuclein induce pathogenic activation of human midbrain astrocytes, involving inflammatory responses, downregulation of phagocytic function, and conferral of neurotoxic activity. These effects are dependent on necroptotic kinases RIPK1 and RIPK3, but do not involve MLKL or necroptosis. The activation of astrocytes occurs through RIPK-dependent activation of NF-kappa B signaling, highlighting new roles for RIP kinase signaling in regulating glial cell biology and neuroinflammation, with implications for Parkinsonian neurodegeneration.