Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling

Nydia P. Chang; Evan M. DaPrano; Marissa Lindman; Irving Estevez; Tsui Wen Chou; Wesley R. Evans; Marialaina Nissenbaum; Micheal McCourt; Diego Alzate; Colm Atkins; Alexander W. Kusnecov; Rafiq Huda; Brian P. Daniels

doi:10.1172/jci.insight.177002

Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling

Nydia P. Chang, Evan M. DaPrano, Marissa Lindman, Irving Estevez, Tsui Wen Chou, Wesley R. Evans, Marialaina Nissenbaum, Micheal McCourt, Diego Alzate, Colm Atkins, Alexander W. Kusnecov, Rafiq Huda, Brian P. Daniels

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	e177002
Journal	JCI Insight
Volume	9
Issue number	11
DOIs	https://doi.org/10.1172/jci.insight.177002
State	Published - Jun 10 2024

ASJC Scopus subject areas

General Medicine

Access to Document

10.1172/jci.insight.177002

Cite this

@article{8764867c001041578c92f12196adc639,

title = "Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling",

abstract = "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{\textquoteright}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.",

author = "Chang, {Nydia P.} and DaPrano, {Evan M.} and Marissa Lindman and Irving Estevez and Chou, {Tsui Wen} and Evans, {Wesley R.} and Marialaina Nissenbaum and Micheal McCourt and Diego Alzate and Colm Atkins and Kusnecov, {Alexander W.} and Rafiq Huda and Daniels, {Brian P.}",

note = "Publisher Copyright: {\textcopyright} 2024, Chang et al.",

year = "2024",

month = jun,

day = "10",

doi = "10.1172/jci.insight.177002",

language = "English (US)",

volume = "9",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "11",

}

TY - JOUR

T1 - Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling

AU - Chang, Nydia P.

AU - DaPrano, Evan M.

AU - Lindman, Marissa

AU - Estevez, Irving

AU - Chou, Tsui Wen

AU - Evans, Wesley R.

AU - Nissenbaum, Marialaina

AU - McCourt, Micheal

AU - Alzate, Diego

AU - Atkins, Colm

AU - Kusnecov, Alexander W.

AU - Huda, Rafiq

AU - Daniels, Brian P.

PY - 2024/6/10

Y1 - 2024/6/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85195668526&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85195668526&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.177002

DO - 10.1172/jci.insight.177002

M3 - Article

C2 - 38713518

SN - 2379-3708

VL - 9

JO - JCI Insight

JF - JCI Insight

IS - 11

M1 - e177002

ER -

Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Cite this