| First Author | Sterling JK | Year | 2022 |
| Journal | Cell Rep | Volume | 38 |
| Issue | 7 | Pages | 110358 |
| PubMed ID | 35172141 | Mgi Jnum | J:324659 |
| Mgi Id | MGI:6879570 | Doi | 10.1016/j.celrep.2022.110358 |
| Citation | Sterling JK, et al. (2022) Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological alpha-synuclein. Cell Rep 38(7):110358 |
| abstractText | alpha-synuclein (alpha-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 alpha-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 alpha-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. |
