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.

Autor: Ghatak S; Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA., Diedrich JK; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA., Talantova M; Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA., Bhadra N; Quantitative Medicine and Systems Biology, The Translational Genomics Research Institute, Phoenix, AZ, 85004, USA., Scott H; Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA., Sharma M; Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA., Albertolle M; Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA., Schork NJ; Quantitative Medicine and Systems Biology, The Translational Genomics Research Institute, Phoenix, AZ, 85004, USA., Yates JR 3rd; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA., Lipton SA; Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA.; Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Aug; Vol. 11 (29), pp. e2400545. Date of Electronic Publication: 2024 May 21.
DOI: 10.1002/advs.202400545
Abstrakt: 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.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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