Emerging Ferroptosis Involvement in Amyotrophic Lateral Sclerosis Pathogenesis: Neuroprotective Activity of Polyphenols

Abstract

Neurodegenerative diseases are a group of diseases that share common features, such as the generation of misfolded protein deposits and increased oxidative stress. Among them, amyotrophic lateral sclerosis (ALS), whose pathogenesis is still not entirely clear, is a complex neurodegenerative disease linked both to gene mutations affecting different proteins, such as superoxide dismutase 1, Tar DNA binding protein 43, Chromosome 9 open frame 72, and Fused in Sarcoma, and to altered iron homeostasis, mitochondrial dysfunction, oxidative stress, and impaired glutamate metabolism. The purpose of this review is to highlight the molecular targets common to ALS and ferroptosis. Indeed, many pathways implicated in the disease are hallmarks of ferroptosis, a recently discovered type of iron-dependent programmed cell death characterized by increased reactive oxygen species (ROS) and lipid peroxidation. Iron accumulation results in mitochondrial dysfunction and increased levels of ROS, lipid peroxidation, and ferroptosis triggers; in addition, the inhibition of the Xc^- system results in reduced cystine levels and glutamate accumulation, leading to excitotoxicity and the inhibition of GPx4 synthesis. These results highlight the potential involvement of ferroptosis in ALS, providing new molecular and biochemical targets that could be exploited in the treatment of the disease using polyphenols.

Keywords: cell death; glutathione peroxidase 4; natural compounds; neurodegenerative diseases; oxidative stress; system Xc−.

Figure 1

The main pathophysiological processes involved in ALS. The pathophysiological processes of the disease are complex, and several mechanisms contribute to neurodegeneration, with multiple sequential steps. The onset of pathology appears to be due to a heterogenous interaction of genetic, epigenetic, and environmental factors.

Figure 2

Ferroptosis can be triggered by several pathways; one of these involves transferrin, following the release of iron from the internalized protein after its binding to transferrin receptor 1 (TfR1). Cytosolic iron accumulation causes excessive ROS generation via the Fenton reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + ·OH + OH⁻), altering the delicate balance between the physiological and pathophysiological roles of ROS. Highly reactive hydroxyl radicals (·OH) interact with polyunsaturated lipids, triggering lipid peroxidation and damaging membrane integrity. Hydroperoxide radical production is also linked to the action of lipoxygenases (LOXs), which catalyze stereospecific oxygen addition to long chain fatty acids (PUFAs). Specifically, acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) catalyzes the addition of Coenzyme A to fatty acids to produce PUFA-CoAs, which are utilized by lysophosphatidylcholine acyltransferase 3 (LPCAT3) to produce PUFA-PE, promoting lipid peroxidation. Another pathway could involve the inhibition of system Xc⁻, a membrane transporter that allows the exchange of cystine and glutamate in and out of the cell. The inhibition of the transporter causes a reduction in cystine in the cellular environment that results in GSH synthesis, and consequently reduced GPx4 efficiency. This enzyme prevents lipid peroxidation, neutralizing hydroperoxides through GSH oxidation. Up and down red arrows indicate the increase and decrease of concentration, respectively.

Figure 3

Implications of ferroptosis in the biochemical progression of ALS. Iron accumulation causes mitochondrial dysfunction and increased levels of ROS, lipid peroxidation, and ferroptosis. Inhibition of the Xc⁻ system causes decreased levels of cystine and the accumulation of glutamate, which on the one hand results in excitotoxicity and on the other hand in inhibited GPx4 synthesis, promoting lipid peroxidation. The occurrence of these events causes increased pathology and cellular death. Up and down red arrows indicate the increase and decrease of concentration, respectively.