Inferring protein expression changes from mRNA in Alzheimer’s dementia using deep neural networks

Journal Article · 02 February 2022 · Nature Communications

DOI: https://doi.org/10.1038/s41467-022-28280-1 · OSTI ID:2471628

Tasaki, Shinya  ^[1]; Xu, Jishu ^[1]; Avey, Denis R. ^[1]; Johnson, Lynnaun ^[1]; Petyuk, Vladislav A.  ^[2]; Dawe, Robert J. ^[1]; Bennett, David A. ^[1]; Wang, Yanling ^[1]; Gaiteri, Chris ^[1]

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1. Rush University Medical Center, Chicago, IL (United States)
2. Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Identifying the molecular systems and proteins that modify the progression of Alzheimer’s disease and related dementias (ADRD) is central to drug target selection. However, discordance between mRNA and protein abundance, and the scarcity of proteomic data, has limited our ability to advance candidate targets that are mainly based on gene expression. Therefore, by using a deep neural network that predicts protein abundance from mRNA expression, here we attempt to track the early protein drivers of ADRD. Specifically, by applying the clei2block deep learning model to 1192 brain RNA-seq samples, we identify protein modules and disease-associated expression changes that were not directly observed at the mRNA level. Moreover, pseudo-temporal trajectory inference based on the predicted proteome became more closely correlated with cognitive decline and hippocampal atrophy compared to RNA-based trajectories. This suggests that the predicted changes in protein expression could provide a better molecular representation of ADRD progression. Furthermore, overlaying clinical traits on protein pseudotime trajectory identifies protein modules altered before cognitive impairment. These results demonstrate how our method can be used to identify potential early protein drivers and possible drug targets for treating and/or preventing ADRD.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
• Sponsoring Organization: National Institutes of Health (NIH); USDOE
• Grant/Contract Number: AC05-76RL01830
• OSTI ID: 2471628
• Journal Information: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 13; ISSN 2041-1723
• Publisher: Nature Publishing GroupCopyright Statement
• Country of Publication: United States
• Language: English