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

a-synuclein (a-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 a-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 a-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.

Automated summary

The aggregation and accumulation of a-synuclein drive neurodegeneration in Parkinson's disease (PD). Microglia activated by misfolded a-synuclein release interleukin 6 (IL-6), which induces changes in neuronal iron transcriptome and leads to cellular iron accumulation. The IL-6-mediated cellular iron sequestration response (CISR) contributes to synuclein-induced neurodegeneration in PD patients.