Ferroptosis-Related Genes in Neurodevelopment and Central Nervous System

Abstract

Ferroptosis, first introduced as a new form of regulated cell death induced by erastin, is accompanied by the accumulation of iron and lipid peroxides, thus it can be inhibited either by iron chelators or by lipophilic antioxidants. In the past decade, multiple studies have introduced the potential importance of ferroptosis in many human diseases, including cancer and neurodegenerative diseases. In this review, we will discuss the genetic association of ferroptosis with neurological disorders and development of the central nervous system.

Keywords: CNS; brain development; ferroptosis; iron; lipid peroxides; neurological disorder.

Figure 1

Mechanism of ferroptosis. Iron-dependent accumulation of lipid peroxides promotes ROS production, causing ferroptosis. By-products of the mevalonate pathway and glutathione metabolism, however, can rescue ferroptosis.

Figure 2

Heatmap of upregulated ferroptosis genes tested against BrainSpan developmental stage. A total of 14 ferroptosis (FR) gene sets displayed significant temporal enrichment in BrainSpan data: NCOA4, POR, PROM2, AIFM2, TFRC, MAP1LC3B, MAP1LCA, HMOX1, YAP1, NFE2L2, SLC7A11, TF, EPAS1, and GCLC. These are gene sets with FR genes from module groups 2, 3, and 5. Statistically significant results (−log₁₀ adjusted p-value ≤ 0.05) are marked with stars (*). Abbreviations: pcw, post conceptional weeks; mos, postnatal months; yrs, postnatal years.

Figure 3

Ferroptosis gene expressions in the cortices of the adolescent mouse brain. Distributions of FR genes were described for various cell types in the mouse brain. Cell types, including neurons, oligodendrocytes, or other non-neuronal cells are described as a cluster of cells using the t-distributed stochastic neighbor embedding (t-SNE), a probabilistic method for visualizing high dimensional single cell RNA-sequencing data. Among FR genes that are converted to mouse genes, five genes (Epas1, Map1lc3a, Map1lc3b, Tfrc, Trf) with postnatal rising trajectory were used. Only clusters with markers that intersected with FR genes are colored, according to the expression levels, which are log₂ transformed. Clusters that are not of interest in each plot are colored in light gray. (A) t-SNE plot in anterior cortex; (B) middle cortex; (C) posterior cortex.

Figure 4

Ferroptosis gene expressions in the mouse brain. (A) Results of in situ hybridization (ISH) experiments localizing FR gene expressions in the cortices of the P56 mouse brain of Allen Brain ISH Atlas [137]. (B) t-SNE plot of cells expressing FR genes across the developing mouse brain, using the UCSC Cell Browser and the single cell RNA-sequencing data of Manno et al. [138]. Cell types are annotated inside the plots.