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

Authors
JK Sterling, TI Kam, S Guttha et al

Lab
University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

Journal
Cell Reports

Abstract
Alpha-synuclein (alpha-syn) aggregation and accumulation driveÊneurodegenerationÊinÊParkinson's diseaseÊ(PD). TheÊsubstantia nigraÊof patients with PD contains excess iron, yet the underlying mechanism accounting for this iron accumulation is unclear. Here, we show that misfolded _-syn activatesÊmicroglia, which release interleukin 6 (IL-6). IL-6, via itsÊtrans-signaling pathway, induces changes in the neuronal ironÊtranscriptomeÊthat 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.ÊGenetic deletionÊof IL-6, or treatment with the iron chelatorÊdeferiprone, reduces pathological _-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.

BIOSEB Instruments Used:
Grip strength test (BIO-GS3)