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© 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Standard single-cell (sc) proteomics of disease states inferred from multicellular organs or organoids cannot currently be related to single-cell physiology. Here, a scPatch-Clamp/Proteomics platform is developed on single neurons generated from hiPSCs bearing an Alzheimer's disease (AD) genetic mutation and compares them to isogenic wild-type controls. This approach provides both current and voltage electrophysiological data plus detailed proteomics information on single-cells. With this new method, the authors are able to observe hyperelectrical activity in the AD hiPSC-neurons, similar to that observed in the human AD brain, and correlate it to ≈1400 proteins detected at the single neuron level. Using linear regression and mediation analyses to explore the relationship between the abundance of individual proteins and the neuron's mutational and electrophysiological status, this approach yields new information on therapeutic targets in excitatory neurons not attainable by traditional methods. This combined patch-proteomics technique creates a new proteogenetic-therapeutic strategy to correlate genotypic alterations to physiology with protein expression in single-cells.

Details

Title
Single-Cell Patch-Clamp/Proteomics of Human Alzheimer's Disease iPSC-Derived Excitatory Neurons Versus Isogenic Wild-Type Controls Suggests Novel Causation and Therapeutic Targets
Author
Ghatak, Swagata 1 ; Diedrich, Jolene K 2 ; Talantova, Maria 1 ; Bhadra, Nivedita 3 ; Scott, Henry 1 ; Sharma, Meetal 1 ; Albertolle, Matthew 1 ; Schork, Nicholas J 3 ; Yates, John R, III 2 ; Lipton, Stuart A 4   VIAFID ORCID Logo 

 Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA 
 Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA 
 Quantitative Medicine and Systems Biology, The Translational Genomics Research Institute, Phoenix, AZ, USA 
 Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA; Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA 
Section
Research Article
Publication year
2024
Publication date
Aug 2024
Publisher
John Wiley & Sons, Inc.
e-ISSN
21983844
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3089810199
Copyright
© 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.