Roles for astrocytic RIPK3 signaling in Parkinson's disease pathogenesis

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Abstract Parkinson’s disease (PD) is a neurodegenerative disorder of global concern, imposing an estimated cost of $52 billion per year in the United States, alone. The pathological hallmarks of PD include debilitating motor deficits, driven by progressive degeneration of dopaminergic neurons in the nigrostriatal pathway, an essential circuit for motor function. Emerging evidence suggests that neuroinflammation is a key player in the pathophysiology of this degenerative process. Astrocytes are the most abundant glial cells in the central nervous system (CNS), where they serve diverse homeostatic functions. However, following inflammatory stimulation, astrocytes enter a reactive state that can be neurotoxic, resulting in neuronal cell death. Numerous studies have now revealed that reactive astrocytes can contribute to clinical neurodegenerative diseases. However, the mechanism through which homeostatic astrocytes become reactive require further investigation. The central purpose of this proposal is to identify cellular and molecular mechanisms that promote astrocyte activation in the context of neurodegeneration. Recent work from our laboratory and others has identified receptor-interacting protein kinase-3 (RIPK3) as a central mediator of neuroinflammation. Here, we hypothesize that inflammatory RIPK3 signaling can induce astrocyte activation, leading to downstream neurotoxic effects and neuron loss in the midbrain. To test this hypothesis, I will utilize novel mouse genetic systems in which RIPK3 can be specifically deleted, overexpressed, or selectively activated in astrocytes. Studies in Aim 1 will examine how RIPK3 activity in astrocytes shapes transcriptional and functional responses associated with neurotoxic astrocyte activation. Aim 2 will examine whether astrocytic RIPK3 signaling can drive key molecular features of PD pathogenesis, including dopaminergic axon degeneration and reduction of dopamine release in the striatum. Together, these experiments aim to identify RIPK3 signaling as a vital mechanism of neurotoxic astrocyte activation and establish roles for this pathway in the pathophysiology of PD. Identifying these cell type-specific molecular mechanisms of Parkinsonian neurodegeneration are of vital importance for developing targeted PD therapeutics.