1. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration
- Author
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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 MY, Gong, Shiaoching, Manfredi, Giovanni, Coppola, Giovanni, Krogan, Nevan J, Geschwind, Daniel H, and Gan, Li
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Alzheimer's Disease Related Dementias (ADRD) ,Brain Disorders ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Dementia ,Aging ,Frontotemporal Dementia (FTD) ,Stem Cell Research - Induced Pluripotent Stem Cell ,Stem Cell Research ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative ,Alzheimer's Disease ,Neurosciences ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Alzheimer Disease ,Amino Acids ,Biotinylation ,Brain ,Cell Nucleus ,Disease Progression ,Energy Metabolism ,Frontotemporal Dementia ,Humans ,Induced Pluripotent Stem Cells ,Mitochondria ,Mutant Proteins ,Mutation ,Nerve Degeneration ,Neurons ,Protein Binding ,Protein Domains ,Protein Interaction Maps ,Proteomics ,Severity of Illness Index ,Subcellular Fractions ,Synapses ,Tauopathies ,tau Proteins ,APEX ,Tau ,Tau secretion ,affinity purification mass spectrometry ,interactome ,mitochondria ,neurodegeneration ,protein-protein interaction ,synapse ,tauopathies ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
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.
- Published
- 2022