Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration

Tara E. Tracy, Jesus Madero-Pérez, Danielle L. Swaney, Timothy S. Chang, Michelle Moritz, Csaba Konrad, Michael E. Ward, Erica Stevenson, Ruth Hüttenhain, Grant Kauwe, Maria Mercedes, Lauren Sweetland-Martin, Xu Chen, Sue Ann Mok, Man Ying Wong, Maria Telpoukhovskaia, Sang Won Min, Chao Wang, Peter Dongmin Sohn, Jordie MartinYungui Zhou, Wenjie Luo, John Q. Trojanowski, Virginia M.Y. Lee, Shiaoching Gong, Giovanni Manfredi, Giovanni Coppola, Nevan J. Krogan, Daniel H. Geschwind, Li Gan

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

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.

Original languageEnglish
Pages (from-to)712-728.e14
JournalCell
Volume185
Issue number4
DOIs
StatePublished - 17 Feb 2022
Externally publishedYes

Keywords

  • APEX
  • Tau
  • Tau secretion
  • affinity purification mass spectrometry
  • interactome
  • mitochondria
  • neurodegeneration
  • protein-protein interaction
  • synapse
  • tauopathies

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