Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein

Jacob K. Sterling; Tae In Kam; Samyuktha Guttha; Hyejin Park; Bailey Baumann; Amir A. Mehrabani-Tabari; Hannah Schultz; Brandon Anderson; Ahab Alnemri; Shih Ching Chou; Juan C. Troncoso; Valina L. Dawson; Ted M. Dawson; Joshua L. Dunaief

doi:10.1016/j.celrep.2022.110358

Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein

Jacob K. Sterling, Tae In Kam, Samyuktha Guttha, Hyejin Park, Bailey Baumann, Amir A. Mehrabani-Tabari, Hannah Schultz, Brandon Anderson, Ahab Alnemri, Shih Ching Chou, Juan C. Troncoso, Valina L. Dawson, Ted M. Dawson, Joshua L. Dunaief

School of Medicine

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

Abstract

α-synuclein (α-syn) aggregation and accumulation drive neurodegeneration in Parkinson's disease (PD). The substantia nigra of patients with PD contains excess iron, yet the underlying mechanism accounting for this iron accumulation is unclear. Here, we show that misfolded α-syn activates microglia, which release interleukin 6 (IL-6). IL-6, via its trans-signaling pathway, induces changes in the neuronal iron transcriptome that promote ferrous iron uptake and decrease cellular iron export via a pathway we term the cellular iron sequestration response, or CISR. The brains of patients with PD exhibit molecular signatures of the IL-6-mediated CISR. Genetic deletion of IL-6, or treatment with the iron chelator deferiprone, reduces pathological α-syn toxicity in a mouse model of sporadic PD. These data suggest that IL-6-induced CISR leads to toxic neuronal iron accumulation, contributing to synuclein-induced neurodegeneration.

Original language	English (US)
Article number	110358
Journal	Cell Reports
Volume	38
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2022.110358
State	Published - Feb 15 2022

Keywords

Parkinson's disease
cellular iron sequestration response
interleukin 6
iron
microglia
neurodegeneration
neuroinflammation
α-synuclein

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2022.110358

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Sterling, J. K., Kam, T. I., Guttha, S., Park, H., Baumann, B., Mehrabani-Tabari, A. A., Schultz, H., Anderson, B., Alnemri, A., Chou, S. C., Troncoso, J. C., Dawson, V. L., Dawson, T. M., & Dunaief, J. L. (2022). Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein. Cell Reports, 38(7), Article 110358. https://doi.org/10.1016/j.celrep.2022.110358

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title = "Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein",

abstract = "α-synuclein (α-syn) aggregation and accumulation drive neurodegeneration in Parkinson's disease (PD). The substantia nigra of patients with PD contains excess iron, yet the underlying mechanism accounting for this iron accumulation is unclear. Here, we show that misfolded α-syn activates microglia, which release interleukin 6 (IL-6). IL-6, via its trans-signaling pathway, induces changes in the neuronal iron transcriptome that promote ferrous iron uptake and decrease cellular iron export via a pathway we term the cellular iron sequestration response, or CISR. The brains of patients with PD exhibit molecular signatures of the IL-6-mediated CISR. Genetic deletion of IL-6, or treatment with the iron chelator deferiprone, reduces pathological α-syn toxicity in a mouse model of sporadic PD. These data suggest that IL-6-induced CISR leads to toxic neuronal iron accumulation, contributing to synuclein-induced neurodegeneration.",

keywords = "Parkinson's disease, cellular iron sequestration response, interleukin 6, iron, microglia, neurodegeneration, neuroinflammation, α-synuclein",

author = "Sterling, {Jacob K.} and Kam, {Tae In} and Samyuktha Guttha and Hyejin Park and Bailey Baumann and Mehrabani-Tabari, {Amir A.} and Hannah Schultz and Brandon Anderson and Ahab Alnemri and Chou, {Shih Ching} and Troncoso, {Juan C.} and Dawson, {Valina L.} and Dawson, {Ted M.} and Dunaief, {Joshua L.}",

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year = "2022",

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doi = "10.1016/j.celrep.2022.110358",

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T1 - Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein

AU - Sterling, Jacob K.

AU - Kam, Tae In

AU - Guttha, Samyuktha

AU - Park, Hyejin

AU - Baumann, Bailey

AU - Mehrabani-Tabari, Amir A.

AU - Schultz, Hannah

AU - Anderson, Brandon

AU - Alnemri, Ahab

AU - Chou, Shih Ching

AU - Troncoso, Juan C.

AU - Dawson, Valina L.

AU - Dawson, Ted M.

AU - Dunaief, Joshua L.

PY - 2022/2/15

Y1 - 2022/2/15

N2 - α-synuclein (α-syn) aggregation and accumulation drive neurodegeneration in Parkinson's disease (PD). The substantia nigra of patients with PD contains excess iron, yet the underlying mechanism accounting for this iron accumulation is unclear. Here, we show that misfolded α-syn activates microglia, which release interleukin 6 (IL-6). IL-6, via its trans-signaling pathway, induces changes in the neuronal iron transcriptome that promote ferrous iron uptake and decrease cellular iron export via a pathway we term the cellular iron sequestration response, or CISR. The brains of patients with PD exhibit molecular signatures of the IL-6-mediated CISR. Genetic deletion of IL-6, or treatment with the iron chelator deferiprone, reduces pathological α-syn toxicity in a mouse model of sporadic PD. These data suggest that IL-6-induced CISR leads to toxic neuronal iron accumulation, contributing to synuclein-induced neurodegeneration.

AB - α-synuclein (α-syn) aggregation and accumulation drive neurodegeneration in Parkinson's disease (PD). The substantia nigra of patients with PD contains excess iron, yet the underlying mechanism accounting for this iron accumulation is unclear. Here, we show that misfolded α-syn activates microglia, which release interleukin 6 (IL-6). IL-6, via its trans-signaling pathway, induces changes in the neuronal iron transcriptome that promote ferrous iron uptake and decrease cellular iron export via a pathway we term the cellular iron sequestration response, or CISR. The brains of patients with PD exhibit molecular signatures of the IL-6-mediated CISR. Genetic deletion of IL-6, or treatment with the iron chelator deferiprone, reduces pathological α-syn toxicity in a mouse model of sporadic PD. These data suggest that IL-6-induced CISR leads to toxic neuronal iron accumulation, contributing to synuclein-induced neurodegeneration.

KW - Parkinson's disease

KW - cellular iron sequestration response

KW - interleukin 6

KW - iron

KW - microglia

KW - neurodegeneration

KW - neuroinflammation

KW - α-synuclein

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Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein

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