Abstract
Amyotropic lateral sclerosis (ALS) is a lethally progressive and irreversible neurodegenerative disease marked by apparent death of motor neurons present in the spinal cord, brain stem and motor cortex. While more and more gene mutants being established for genetic ALS, the vast majority suffer from sporadic ALS (>90%). It has been challenging, thus, to model sporadic ALS which is one reason why the underlying pathophysiology remains elusive and has stalled the development of therapeutic strategies of this progressive motor neuron disease. To further unravel these pathological signaling pathways, human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs) from FUS- and SOD1 ALS patients and healthy controls were systematically compared to independent published datasets. Here through this study we created a gene profile of ALS by analyzing the DEGs, the Kyoto encyclopedia of Genes and Genomes (KEGG) pathways, the interactome and the transcription factor profiles (TF) that would identify altered molecular/functional signatures and their interactions at both transcriptional (mRNAs) and translational levels (hub proteins and TFs). Our findings suggest that FUS and SOD1 may develop from dysregulation in several unique pathways and herpes simplex virus (HSV) infection was among the topmost predominant cellular pathways connected to FUS and not to SOD1. In contrast, SOD1 is mainly characterized by alterations in the metabolic pathways and alterations in the neuroactive-ligand–receptor interactions. This suggests that different genetic ALS forms are singular diseases rather than part of a common spectrum. This is important for patient stratification clearly pointing towards the need for individualized medicine approaches in ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a lethally progressive and irreversible neurodegenerative disease characterized by selective loss of motor neurons in the motor cortex, brain stem and spinal cord
We analyzed our gene expression datasets of iPSC-derived motor neurons (MNs) at day three in vitro (DIV) 14 of terminal differentiation (=total DIV 30, Figure S1) since major structural degeneration appeared from DIV 16 of motor neuron differentiation (=total DIV 32) onwards [25], and compared them to the NCBI Gene Expression Omnibus (GEO) GSE106382 [23] (FUS- and superoxide dismutase 1 (SOD1)-ALS and controls) dataset contained data from ALS patients versus healthy controls (DIV35, prior neurodegeneration became obvious)
We first compared all the differentially expressed genes (DEGs) together among fused in sarcoma protein (FUS)- and SOD1-ALS datasets and our analysis showed that gene expression profiles of subjects with FUS and SOD1 did not overlap with those affected by FUS and SOD1 (GEO dataset) (Figure 1B); significant overlaps of DEGs were identified when systematically comparing them with their respective or mutual counterparts, suggesting that similar functional and/or molecular changes occur in these disease subtypes
Summary
Amyotrophic lateral sclerosis (ALS) is a lethally progressive and irreversible neurodegenerative disease characterized by selective loss of motor neurons in the motor cortex, brain stem and spinal cord. Several studies in ALS patients and model systems have identified numerous genes in ALS pathogenesis, among which four major genes, chromosome 9 open reading frame 72 (C9ORF72), superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TARDBP) and mutations in fused in sarcoma protein (FUS), are largely responsible for genetic forms of ALS [7,8]. These causal genes affect diverse processes, including RNA metabolism, protein misfolding, mitochondrial dysfunction, cytoskeletal abnormalities, impaired axonal transport, inflammation and apoptosis [9,10,11,12,13]. Till date, there is no cure for ALS, and understanding the molecular signatures of neurodegeneration in ALS can lead to the identification of potential biomarkers that might improve early diagnosis and aid in the identification of therapeutic targets
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