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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\u2010layered 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\u20103\u03b2), as common modifiers. We validated these modifiers with the help of four\n                    <jats:italic>Drosophila<\/jats:italic>\n                    ND models. Further evaluation of Akt1 in human cell\u2010based 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\u2010term 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\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/ssbio.cau.ac.kr\/software\/mlnet\" ext-link-type=\"uri\">http:\/\/ssbio.cau.ac.kr\/software\/mlnet<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.15252\/msb.202311801","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T17:01:56Z","timestamp":1700586116000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["A multi\u2010layered network model identifies Akt1 as a common modulator of neurodegeneration"],"prefix":"10.1038","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9107-7040","authenticated-orcid":false,"given":"Dokyun","family":"Na","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2054-1416","authenticated-orcid":false,"given":"Do\u2010Hwan","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7664-6639","authenticated-orcid":false,"given":"Jae\u2010Sang","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyang\u2010Mi","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daeahn","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myeong\u2010Sang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilal","family":"Shaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bomi","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6015-9393","authenticated-orcid":false,"given":"Jae Gwang","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5544-0503","authenticated-orcid":false,"given":"Yuna","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyungeun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4242-0818","authenticated-orcid":false,"given":"Kwang\u2010Seok","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0933-4022","authenticated-orcid":false,"given":"Mi Young","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Seok","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han Saem","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang\u2010Hee","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M","family":"Bui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0060-6884","authenticated-orcid":false,"given":"Kangseok","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyung Wook","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6709-3809","authenticated-orcid":false,"given":"Young Sik","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3672-6594","authenticated-orcid":false,"given":"J\u00f6rg","family":"Gsponer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,20]]},"reference":[{"key":"BFMSB202311801_CR1","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nbt1203","volume":"24","author":"S Aerts","year":"2006","unstructured":"Aerts S, Lambrechts D, Maity S, Van Loo P, Coessens B, De Smet F, Tranchevent LC, De Moor B, Marynen P, Hassan B et\u00a0al (2006) Gene prioritization through genomic data fusion. 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