Iron reduces the propagation of pathological α‐synuclein

Abstract

Elevated iron and pathological α-synuclein (the main component of Lewy bodies) are common features of Parkinson's disease (PD), however, whether they are mechanistically related is uncertain.α-synuclein has been shown to bind to iron in vitro, which accelerates its aggregation into fibrils (Golts et al., 2002). Iron enrichment of Lewy bodies reveals the potential for this interaction to be of pathological significance (Ayton & Lei, 2014). It is possible that iron may interact with α-synuclein to cause neurodegeneration in PD by the iron-dependent cell death pathway termed ferroptosis (Yan et al., 2021). While aggregated α-synuclein was shown not to induce ferroptosis in neuroblastoma cells (Guiney et al., 2020), and α-synuclein toxicity was abolished by inhibitors of ferroptosis in induced pluripotent stem cell (iPSC)-derived neurons (Angelova et al., 2020). Lewy body pathology has been shown to be transmitted between brain regions (Hijaz & Volpicelli-Daley, 2020), it remains unknown what impact iron may have on this pathology spreading. In a recent study published in the Journal of Neurochemistry, Joppe and colleagues (Joppe et al., 2021) found that in a mouse model of intrastriatal α-synuclein preformed fibrils (PFFs) injection, the propagation of pathological α-synuclein marked as αsynuclein phosphorylated at serine 129 (pS129) was decreased in mice that had brain iron elevation induced by neonatal iron feeding (Figure 1). The long-term memory but not motor function