Stanford Advisors

All Publications

  • Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN NEUROBIOLOGY OF DISEASE Nogami, M., Ishikawa, M., Doi, A., Sano, O., Sone, T., Akiyama, T., Aoki, M., Nakanishi, A., Ogi, K., Yano, M., Okano, H. 2021; 155: 105364


    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.

    View details for DOI 10.1016/j.nbd.2021.105364

    View details for Web of Science ID 000663807700001

    View details for PubMedID 33857636

  • Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations STEM CELL REPORTS Mitsuzawa, S., Suzuki, N., Akiyama, T., Ishikawa, M., Sone, T., Kawada, J., Funayama, R., Shirota, M., Mitsuhashi, H., Morimoto, S., Ikeda, K., Shijo, T., Ohno, A., Nakamura, N., Ono, H., Ono, R., Osana, S., Nakagawa, T., Nishiyama, A., Izumi, R., Kaneda, S., Ikeuchi, Y., Nakayama, K., Fujii, T., Warita, H., Okano, H., Aoki, M. 2021; 16 (6): 1527-1541


    Amyotrophic lateral sclerosis (ALS) is an adult-onset incurable motor neuron (MN) disease. The reasons for selective MN vulnerability in ALS are unknown. Axonal pathology is among the earliest signs of ALS. We searched for novel modulatory genes in human MN axon shortening affected by TARDBP mutations. In transcriptome analysis of RNA present in the axon compartment of human-derived induced pluripotent stem cell (iPSC)-derived MNs, PHOX2B (paired-like homeobox protein 2B) showed lower expression in TARDBP mutant axons, which was consistent with axon qPCR and in situ hybridization. PHOX2B mRNA stability was reduced in TARDBP mutant MNs. Furthermore, PHOX2B knockdown reduced neurite length in human MNs. Finally, phox2b knockdown in zebrafish induced short spinal axons and impaired escape response. PHOX2B is known to be highly express in other types of neurons maintained after ALS progression. Collectively, TARDBP mutations induced loss of axonal resilience, which is an important ALS-related phenotype mediated by PHOX2B downregulation.

    View details for DOI 10.1016/j.stemcr.2021.04.021

    View details for Web of Science ID 000659201500014

    View details for PubMedID 34048688

    View details for PubMedCentralID PMC8190591