Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration

Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA...

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Bibliographic Details
Published in:Cell 2022-02, Vol.185 (4), p.712-728.e14
Main Authors: Tracy, Tara E., Madero-Pérez, Jesus, Swaney, Danielle L., Chang, Timothy S., Moritz, Michelle, Konrad, Csaba, Ward, Michael E., Stevenson, Erica, Hüttenhain, Ruth, Kauwe, Grant, Mercedes, Maria, Sweetland-Martin, Lauren, Chen, Xu, Mok, Sue-Ann, Wong, Man Ying, Telpoukhovskaia, Maria, Min, Sang-Won, Wang, Chao, Sohn, Peter Dongmin, Martin, Jordie, Zhou, Yungui, Luo, Wenjie, Trojanowski, John Q., Lee, Virginia M.Y., Gong, Shiaoching, Manfredi, Giovanni, Coppola, Giovanni, Krogan, Nevan J., Geschwind, Daniel H., Gan, Li
Format: Article
Language:English
Subjects:
affinity purification mass spectrometry
Alzheimer Disease - genetics
Amino Acids - metabolism
APEX
Biotinylation
Brain - metabolism
Brain - pathology
Cell Nucleus - metabolism
Disease Progression
Energy Metabolism
Frontotemporal Dementia - genetics
Humans
Induced Pluripotent Stem Cells - metabolism
interactome
mitochondria
Mitochondria - metabolism
Mutant Proteins - metabolism
Mutation - genetics
Nerve Degeneration - metabolism
Nerve Degeneration - pathology
neurodegeneration
Neurons - metabolism
Protein Binding
Protein Domains
Protein Interaction Maps
protein-protein interaction
Proteomics
Severity of Illness Index
Subcellular Fractions - metabolism
synapse
Synapses - metabolism
Tau
tau Proteins - chemistry
tau Proteins - metabolism
Tau secretion
tauopathies
Tauopathies - genetics
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Summary:Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of Tau with presynaptic vesicle proteins during activity-dependent Tau secretion and mapped the Tau-binding sites to the cytosolic domains of integral synaptic vesicle proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau’s interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multimodal and dynamic Tau interactomes with exquisite spatial resolution shed light on Tau’s role in neuronal function and disease and highlight potential therapeutic targets to block Tau-mediated pathogenesis. [Display omitted] •APEX-mapped Tau interactome at subcellular and amino acid levels in human neurons•Activity-dependent binding of Tau to synaptic vesicle proteins during Tau secretion•FTD mutations reduce Tau binding to mitochondria proteins and impair bioenergetics•Tau interactors modified by FTD mutation are downregulated in human tauopathy By combining APEX and AP-MS proteomic approaches, Tau interactome mapping reveals that Tau interactors are modified by neuronal activity and FTD mutations in human iPSC-derived neurons.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2021.12.041