A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration

Dokyun Na, Do Hwan Lim, Jae Sang Hong, Hyang Mi Lee, Daeahn Cho, Myeong Sang Yu, Bilal Shaker, Jun Ren, Bomi Lee, Jae Gwang Song, Yuna Oh, Kyungeun Lee, Kwang Seok Oh, Mi Young Lee, Min Seok Choi, Han Saem Choi, Yang Hee Kim, Jennifer M. Bui, Kangseok Lee, Hyung Wook KimYoung Sik Lee, Jörg Gsponer

    Research output: Contribution to journalArticlepeer-review

    2 Citations (Scopus)

    Abstract

    The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi-layered network expansion (MLnet) model to predict protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK-3β), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.

    Original languageEnglish
    Article numbere11801
    JournalMolecular Systems Biology
    Volume19
    Issue number12
    DOIs
    Publication statusPublished - 2023 Dec 6

    Bibliographical note

    Publisher Copyright:
    © 2023 The Authors. Published under the terms of the CC BY 4.0 license.

    Keywords

    • common modifier
    • insulin signaling pathway
    • multi-layered network expansion
    • neurodegenerative diseases
    • proteostasis

    ASJC Scopus subject areas

    • Information Systems
    • General Biochemistry,Genetics and Molecular Biology
    • General Immunology and Microbiology
    • General Agricultural and Biological Sciences
    • Computational Theory and Mathematics
    • Applied Mathematics

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