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Isoprenaline (150 mg/kg s.c., given once (at time 0) or twice, at 0 and 24 h)

The resultant accumulation of labile iron intensifies oxidative stress via Fenton chemistry and ultimately renders dopaminergic neurons highly susceptible to ferroptosis ( Cells export iron via the plasma membrane iron exporter protein, FPN1, the sole identified protein responsible for exporting intracellular iron in mammals ( Ceruloplasmin (CP) is a ferroxidase that is mainly found in a GPI-anchored form on astrocytes, converting toxic Fe 2+ to non-toxic Fe 3+ , physically associating with FPN1 to facilitate iron efflux from central nervous system cells, and inhibiting Fe 2+ -mediated lipid peroxidation by reducing the presence of highly reactive Fe 2+ ( In vitro experiments demonstrated that functionally impaired CP fails to effectively oxidize Fe 2+ , leading to iron ion retention in neuronal cells and promotion of ferroptosis ( Iron regulatory proteins (IRPs), bind to iron-responsive elements (IREs) in the 5 untranslated region (UTR) of mRNAs encoding ferritin and FPN1 to inhibit their translation, while binding to IREs in the 3 UTR of TfR1 and DMT1 mRNAs to stabilize these transcripts, thereby adjusting iron storage, export, and uptake ( 2.1.3 The dual role of NM in iron homeostasis and PD pathology NM-containing neurons in the SNpc and the locus coeruleus are among the most vulnerable and prominently degenerated cell types in PD

These will need to be validated across diverse patient populations, different stages of the disease, and ethnicities

Two of the proteins identified in these experiments, IL-1 sRII and Lyn, were then confirmed to be susceptible to glutathionylation