Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration

• 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
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2021.12.041

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.