Journal article
Characterization of the Tau Interactome in Human Brain Reveals Isoform-Dependent Interaction with 14-3-3 Family Proteins
eNeuro, Vol.10(3), ENEURO.0503-22.2023
03/2023
DOI: 10.1523/ENEURO.0503-22.2023
PMCID: PMC10035768
PMID: 36898832
Abstract
Despite exhibiting tau phosphorylation similar to Alzheimer disease, the human fetal brain is remarkably resilient to tau aggregation and toxicity. To identify potential mechanisms for this resilience, we used co-immunoprecipitation with mass spectrometry to characterize the tau interactome in human fetal, adult, and Alzheimer disease brains. We found significant differences between the tau interactome in fetal and AD brain tissue, with little difference between adult and AD, although these findings are limited by the low throughput and small sample size of these experiments. Differentially interacting proteins were enriched for 14-3-3 domains, and we found that the 14-3-3-β, η, and γ isoforms interacted with phosphorylated tau in Alzheimer disease but not the fetal brain. Since long isoform (4R) tau is only seen in the adult brain and this is one of the major differences between fetal and AD tau, we tested the ability of our strongest hit (14-3-3-β) to interact with 3R and 4R tau using co-immunoprecipitation, mass photometry, and nuclear magnetic resonance (NMR). We found that 14-3-3-β interacts preferentially with phosphorylated 4R tau, forming a complex consisting of two 14-3-3-β molecules to one tau. By NMR, we mapped 14-3-3 binding regions on tau that span the second microtubule binding repeat, which is unique to 4R tau. Our findings suggest that there are isoform-driven differences between the phospho-tau interactome in fetal and Alzheimer disease brain, including differences in interaction with the critical 14-3-3 family of protein chaperones, which may explain, in part, the resilience of fetal brain to tau toxicity.
Aggregation of phosphorylated tau is the final common pathway for neuronal death across multiple neurodegenerative diseases, but the mechanisms that trigger this process remain unclear. The fetal brain shows high levels of potentially toxic phosphorylated tau without apparent adverse effects, and therefore represents an unprecedented, and heretofore unexplored, opportunity to identify age-related mechanisms for tau toxicity. Our results use a novel data set mapping the tau interactome in human fetal, adult, and AD brain to identify splicing-dependent changes in tau interaction with 14-3-3 family chaperone proteins, which represent highly plausible protective mechanisms in the fetal brain.
Details
- Title: Subtitle
- Characterization of the Tau Interactome in Human Brain Reveals Isoform-Dependent Interaction with 14-3-3 Family Proteins
- Creators
- Ryan K Betters - University of IowaEmma Luhmann - Department of Microbiology and Immunology, all at the University of Iowa, Iowa City, IAAmy C Gottschalk - University of IowaZhen Xu - University of IowaMallory R Shin - University of IowaChristopher P Ptak - Nuclear Magnetic Resonance Core Facility, all at the University of Iowa, Iowa City, IAKimberly L Fiock - University of IowaLilliana C Radoshevich - University of IowaMarco M Hefti - Iowa Neuroscience Institute, all at the University of Iowa, Iowa City, IA
- Resource Type
- Journal article
- Publication Details
- eNeuro, Vol.10(3), ENEURO.0503-22.2023
- DOI
- 10.1523/ENEURO.0503-22.2023
- PMID
- 36898832
- PMCID
- PMC10035768
- NLM abbreviation
- eNeuro
- ISSN
- 2373-2822
- eISSN
- 2373-2822
- Grant note
- DOI: 10.13039/100000065, name: HHS | NIH | National Institute of Neurological Disorders and Stroke, award: K23 NS109284; name: Roy J. Carver Foundation; name: Iowa Neuroscience Institute; name: Kwak-Ferguson Fellowship; name: Histochemical Society
- Language
- English
- Date published
- 03/2023
- Academic Unit
- Molecular Physiology and Biophysics; Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Medicine Administration
- Record Identifier
- 9984375352702771
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