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

Cell Rep. 2022 Feb 15;38(7):110358. doi: 10.1016/j.celrep.2022.110358.

Authors

Affiliations

¹ Scheie Eye Institute, F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Medical Scientist Training Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Diana Helis Henry and Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA.
³ Scheie Eye Institute, F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Diana Helis Henry and Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA.
⁸ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Diana Helis Henry and Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA. Electronic address: tdawson@jhmi.edu.
⁹ Scheie Eye Institute, F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: jdunaief@pennmedicine.upenn.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal / drug effects
Disease Models, Animal
Dopaminergic Neurons / drug effects
Dopaminergic Neurons / metabolism
Dopaminergic Neurons / pathology
Female
Interleukin-6 / metabolism*
Iron / metabolism*
Iron Chelating Agents / pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nerve Degeneration / pathology
Neurons / metabolism*
Parkinson Disease / genetics
Parkinson Disease / pathology
Signal Transduction / drug effects
Substantia Nigra / drug effects
Substantia Nigra / pathology
alpha-Synuclein / toxicity*

Substances

Interleukin-6
Iron Chelating Agents
alpha-Synuclein
Iron

Abstract

Publication types

MeSH terms

Substances

Grants and funding