| Autor: |
Chang NP; Department of Cell Biology and Neuroscience., DaPrano EM; Department of Cell Biology and Neuroscience., Lindman M; Department of Cell Biology and Neuroscience., Estevez I; Department of Cell Biology and Neuroscience., Chou TW; Department of Cell Biology and Neuroscience., Evans WR; Department of Cell Biology and Neuroscience.; W. M. Keck Center for Collaborative Neuroscience, and., Nissenbaum M; Department of Psychology, Rutgers University, Piscataway, New Jersey, USA., McCourt M; Department of Cell Biology and Neuroscience., Alzate D; Department of Cell Biology and Neuroscience., Atkins C; Department of Cell Biology and Neuroscience., Kusnecov AW; Department of Psychology, Rutgers University, Piscataway, New Jersey, USA., Huda R; Department of Cell Biology and Neuroscience.; W. M. Keck Center for Collaborative Neuroscience, and., Daniels BP; Department of Cell Biology and Neuroscience. |
| Abstrakt: |
Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. Receptor interacting protein kinase-3 (RIPK3) signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine model of Parkinson's disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of damage-associated molecular pattern signaling. In mechanistic experiments, we showed that factors released from dying neurons signaled through receptor for advanced glycation endproducts to induce astrocytic RIPK3 signaling, which conferred inflammatory and neurotoxic functional activity. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3. |
