Multi-layered network expansion model identifies Akt1 as common modulator of neurodegeneration

The accumulation of 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 relevance for all proteinopathies remain poorly resolved. Here, we introduce a multi-layered network expansion (MLnet) model that predicts protein modifiers that are common to disease groups. When applied to the four NDs, Alzheimer's disease (AD), Huntington's disease, and Spinocerebellar ataxia types 1 and 3, MLnet identifies 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 evaluations in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins that may be involved in the pathophysiology of multiple diseases and have relevance cross disease boundaries.