Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein
Open accessAbstract
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.
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Misfolded proteins and protein aggregates, including tau, Aβ, α-synuclein, mutant huntingtin, TDP-43, SOD1, and FUS induce microglial activation and neuroinflammation.
“Numerous studies have reported that misfolded proteins and protein aggregates, including tau,136–139 Aβ,138,140 α-synuclein,141–144 mutant huntingtin,145 TDP-43,132,146 superoxide dismutase 1 (SOD1),147–149 and fused in sarcoma (FUS)150 induce microglial activation and neuroinflammation.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [143]
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References 38 · Cited by 58
Research works printed but not linked: 1
- Damier P, Hirsch EC, Agid Y, and Graybiel AM (1999). The substantia nigra of the human brainII. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain 122, 1437– 1448. 10430830
- Authors
- 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.
- Affiliations
- University of Pennsylvania Health System (US)
- Johns Hopkins University (US)
- Corresponding author
- Dawson, Ted M.
- Dunaief, Joshua L.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2022-02
- Volume
- 38
- Issue
- 7
- Pages
- 110358
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC8898592
- OpenAlex
- W4213038617
- Cited by
- 58
- References
- 38
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 11 · 2023: 10 · 2022: 5
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- Funders
- National Institute on Aging (P30AG066507)
- National Eye Institute (F30EY032339, R01EY028916, P30EY001583)
- National Institute of Neurological Disorders and Stroke (P50NS038377, R01NS123456)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- interleukin-6, alpha-synuclein aggregation, Parkinson's disease, ferrous iron uptake, iron export, microglial activation, trans-signaling, substantia nigra, deferiprone, neurodegeneration, iron chelation
- MeSH terms
- Animals, Behavior, Animal, Disease Models, Animal, Female, Iron, Iron Chelating Agents, Male, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Neurons, Parkinson Disease, Substantia Nigra, Signal Transduction, Interleukin-6, Mice, alpha-Synuclein, Dopaminergic Neurons
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