TY  - JOUR
AU  - Dash, Banaja
AU  - Hermann, Andreas
TI  - Transcriptomic Alteration in FUS-ALS Points Towards Apoptosis-Rather than Ferroptosis-Related Cell Death Pathway.
JO  - Cells
VL  - 14
IS  - 18
SN  - 2073-4409
CY  - Basel
PB  - MDPI
M1  - DZNE-2025-01127
SP  - 1417
PY  - 2025
AB  - Amyotrophic lateral sclerosis (ALS) is a fatal type of neurodegenerative disease marked by progressive and selective degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. However, the intricate molecular mechanisms underlying primary cell death pathways, including ferroptosis-related genes (FRGs) mediating MN dysfunction in ALS, remain elusive. Ferroptosis, a novel type of iron-dependent cell death with the accumulation of lipid peroxidation products, stands distinct from apoptotic-related stress and other cell death mechanisms. Although growing advances have highlighted the role of iron deposition, apoptosis and alteration of antioxidant systems in ALS pathogenesis, there is little data at the systems biology level. Therefore, we performed a comprehensive bioinformatic analysis of bulk RNA-sequencing (RNA-seq) data by systematically comparing the gene expression profiles from iPSC-derived MNs of ALS patients and healthy controls using our datasets as well as from the GEO database to reveal the role of ferroptosis-related gene alterations in ALS, especially in selective MN vulnerability of FUSED IN SARCOMA (FUS) mutations. In this study, we first identified differentially expressed genes (DEGs) between FUS mutant and healthy controls. Subsequently, the crossover genes between DEGs and FRGs were selected as differentially expressed ferroptosis-related genes (DEFRGs). Functional enrichment and protein-protein interaction (PPI) analysis of DEFRGs identified that DNA damage, stress response and extra cellular matrix (ECM) were the most significantly dysregulated functions/pathways in FUS-ALS causing mutations compared to healthy controls. While GSEA analysis showed enrichment of genes associated with apoptosis, the degree of ferroptosis and iron ion homeostasis/response to iron of FUS MNs was lower. Altogether, our findings may contribute to a better understanding of the relevant role of cell death pathways underlying selective vulnerability of MNs to neurodegeneration in FUS-ALS pathophysiology.
KW  - Ferroptosis: genetics
KW  - Humans
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Apoptosis: genetics
KW  - RNA-Binding Protein FUS: genetics
KW  - RNA-Binding Protein FUS: metabolism
KW  - Transcriptome: genetics
KW  - Motor Neurons: metabolism
KW  - Motor Neurons: pathology
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Gene Expression Profiling
KW  - ALS (Other)
KW  - RNA-sequencing (Other)
KW  - apoptosis (Other)
KW  - differentially expressed genes (Other)
KW  - ferroptosis (Other)
KW  - ferroptosis-related genes (Other)
KW  - gene expression omnibus (Other)
KW  - iPSC (Other)
KW  - motor neuron (Other)
KW  - RNA-Binding Protein FUS (NLM Chemicals)
KW  - FUS protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41002383
C2  - pmc:PMC12468769
DO  - DOI:10.3390/cells14181417
UR  - https://pub.dzne.de/record/281506
ER  -