SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1

Abstract

Ferroptosis is an iron-dependent cell death with the accumulation of lipid peroxidation and dysfunction of antioxidant systems. As the critical regulator, glutathione peroxidase 4 (GPX4) has been demonstrated to be down-regulated in amyotrophic lateral sclerosis (ALS). However, the mechanism of ferroptosis in ALS remains unclear. In this research, bioinformatics analysis revealed a high correlation between ALS, ferroptosis, and Speedy/RINGO cell cycle regulator family member A (SPY1). Lipid peroxidation of ferroptosis in hSOD1G93A cells and mice was generated by TFR1-imported excess free iron, decreased GSH, mitochondrial membrane dysfunction, upregulated ALOX15, and inactivation of GCH1, GPX4. SPY1 is a “cyclin-like” protein that has been proved to enhance the viability of hSOD1G93A cells by inhibiting DNA damage. In our study, the decreased expression of SPY1 in ALS was resulted from unprecedented ubiquitination degradation mediated by MDM2 (a nuclear-localized E3 ubiquitin ligase). Further, SPY1 was identified as a novel ferroptosis suppressor via alleviating lipid peroxidation produced by dysregulated GCH1/BH4 axis (a resistance axis of ferroptosis) and transferrin receptor protein 1 (TFR1)-induced iron. Additionally, neuron-specific overexpression of SPY1 significantly delayed the occurrence and prolonged the survival in ALS transgenic mice through the above two pathways. These results suggest that SPY1 is a novel target for both ferroptosis and ALS.

Ganglioside GM3 Protects Against Abdominal Aortic Aneurysm by Suppressing Ferroptosis

“…24 The accumulated ROS promotes peroxidation of membrane lipids and induces ferroptosis. Moreover, ferroptosis is usually accompanied increased TFR1 expression and decreased TFR1 ubiquitin degradation, 13,40,41 with the changes in TFR1 expression also positively regulating Fe 2+ accumulation. 41 As a substance commonly found on cell membranes, GM3 is known to affect intracellular signaling by interacting with membrane receptors.…”

Pharmacological Inhibition of Ferroptosis as a Therapeutic Target for Neurodegenerative Diseases and Strokes

“…Mutant SOD1 promotes ferroptosis via generating TfR1‐imported excess free iron, decreasing GSH, upregulating ALOX15, and inactivating GCH1 and GPX4 in ALS. [ 243 ] The study also showed that a highly conserved “cyclin‐like” protein, speedy/RINGO cell cycle regulator family member A (SPY1) resists ferroptosis by upregulating GCH1/BH 4 and downregulating TfR1 in ALS. [ 243 ]…”

Ferroptosis-Regulated Cell Death as a Therapeutic Strategy for Neurodegenerative Diseases: Current Status and Future Prospects

“…50 Recent studies suggest that ferroptosis is essential for motor neuron death. 48,51 Matsuo and colleagues have indicated that GPX4 inhibition is lethal to human iPS cell-derived motor neurons (hiMNs), being reversed by vitamin E acetate, iron chelators, and other inhibitors. 52 Additionally, Oakes et al observed that the mutant of TANK-binding kinase 1 (TBK1), a risk gene of ALS, 53 is reversed by Fer-1 or p62 siRNA and, meanwhile, increases KEAP1 expression in NSC-34 cells, meaning that TBK1 mutation could promote ferroptosis via KEAP1/NRF2/p62 signaling.…”