Increased Vulnerability to Ferroptosis in FUS-ALS

Abstract

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxide accumulation, plays a pivotal role in various pathological conditions, including neurodegenerative diseases. While reasonable evidence for ferroptosis exists, e.g., in Parkinson’s disease or Alzheimer’s disease, there are only a few reports on amyotrophic lateral sclerosis (ALS), a fast progressive and incurable neurodegenerative disease characterized by progressive motor neuron degeneration. Interestingly, initial studies have suggested that ferroptosis might be significantly involved in ALS. Key features of ferroptosis include oxidative stress, glutathione depletion, and alterations in mitochondrial morphology and function, mediated by proteins such as GPX4, xCT, ACSL4 FSP1, Nrf2, and TfR1. Induction of ferroptosis involves small molecule compounds like erastin and RSL3, which disrupt system Xc− and GPX4 activity, respectively, resulting in lipid peroxidation and cellular demise. Mutations in fused in sarcoma (FUS) are associated with familial ALS. Pathophysiological hallmarks of FUS-ALS involve mitochondrial dysfunction and oxidative damage, implicating ferroptosis as a putative cell-death pathway in motor neuron demise. However, a mechanistic understanding of ferroptosis in ALS, particularly FUS-ALS, remains limited. Here, we investigated the vulnerability to ferroptosis in FUS-ALS cell models, revealing mitochondrial disturbances and increased susceptibility to ferroptosis in cells harboring ALS-causing FUS mutations. This was accompanied by an altered expression of ferroptosis-associated proteins, particularly by a reduction in xCT expression, leading to cellular imbalance in the redox system and increased lipid peroxidation. Iron chelation with deferoxamine, as well as inhibition of the mitochondrial calcium uniporter (MCU), significantly alleviated ferroptotic cell death and lipid peroxidation. These findings suggest a link between ferroptosis and FUS-ALS, offering potential new therapeutic targets.

Glycolic acid and D-lactate—putative products of DJ-1—restore neurodegeneration in FUS - and SOD1-ALS

“…Alternatively, DJ-1 acts as a protein deglycase, by which it is able to rescue MGO-modified peptides/proteins in the absence of GSH, resulting in the production of both D-and L-lactate (Zhou et al, 2022). Because there is no lack of GSH in case of FUS-ALS mutants (Ismail et al, 2024), we speculate that only the former is of relevance in our cell model. However, this hypothesis awaits its verification in future studies.…”

“…Lipid peroxidation and AGEs occur in the brain during normal aging as well as in Alzheimer's disease (Dei et al, 2002) and also in ALS patient spinal cord motor neurons (Kikuchi et al, 2000(Kikuchi et al, , 2002. FUS-ALS mutations led to increased ROS production and lipid peroxidation as well (Ismail et al, 2024). AGE Nε-(carboxymethyl) lysine levels are elevated in cerebrospinal fluid of ALS patients (Kaufmann et al, 2004).…”

The research landscape of ferroptosis in neurodegenerative disease: a bibliometric analysis

“…Other researchers also explored the susceptibility to ferroptosis in fused in sarcoma-amyotrophic lateral sclerosis cell models, uncovering mitochondrial disturbances and heightened vulnerability to ferroptosis in cells containing amyotrophic lateral sclerosis-causing fused in sarcoma mutations. This result indicates that ferroptosis could play a substantial role in amyotrophic lateral sclerosis (Ismail et al, 2024). Additionally, One study highlights the benefits of dabrafenib in the treatment of multiple sclerosis by showing its ability to inhibit ferroptosis in microglia through the up-regulation of the Axl receptor.…”