SUMMARY
Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of amyotrophic lateral sclerosis (ALS). Mutated FUS causes accumulation of DNA damage and cytosolic stress granule (SG) formation, thereby motor neuron (MN) death. However, key molecular aetiology remains unclear. Here, we applied a novel platform technology, iBRN, “Non-biased” Bayesian gene regulatory network analysis based on induced pluripotent stem cell (iPSC)-derived cell model, to elucidate the molecular aetiology using transcriptome of iPSC-derived MNs harboring FUSH517D. iBRN revealed “hub molecules”, which strongly influenced transcriptome network, such as miR-125b-5p-TIMELESS axis and PRKDC for the molecular aetiology. Next, we confirmed miR-125b-5p-TIMELESS axis in FUSH517D MNs such that miR-125b-5p regulated several DNA repair-related genes including TIMELESS. In addition, we validated both introduction of miR-125b-5p and knocking down of TIMELESS caused DNA damage in the cell culture model. Furthermore, PRKDC was strongly associated with FUS mis-localization into SGs by DNA damage under impaired DNA-PK activity. Collectively, our iBRN strategy provides the first compelling evidence to elucidate molecular aetiology in neurodegenerative diseases.
Highlights
A new platform technology, “iBRN”, Bayesian gene regulatory network analysis based on iPSC cells
iBRN identifies hub molecules to strongly influence the gene network in FUS-ALS
PRKDC specifically acts as a guardian against FUS mis-localization during DNA damage stress
miR-125b-5p-TIMELESS axis regulates DNA repair-related genes in FUS-ALS.
Competing Interest Statement
H.O. is a paid member of the Scientific Advisory Board of San Bio Co., Ltd. H.O.. is a paid member of K Pharma, Inc. M.Y is a scientific advisor of K Pharma, Inc.The other authors declare that they have no conflict of interest.
Footnotes
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