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Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.

TitleTau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.
Publication TypeJournal Article
Year of Publication2022
AuthorsTracy TE, Madero-Pérez J, Swaney DL, Chang TS, Moritz M, Konrad C, Ward ME, Stevenson E, Huttenhain R, Kauwe G, Mercedes M, Sweetland-Martin L, Chen X, Mok S-A, Wong MYing, Telpoukhovskaia M, Min S-W, Wang C, Sohn PDongmin, Martin J, Zhou Y, Luo W, Trojanowski JQ, M Y Lee V, Gong S, Manfredi G, Coppola G, Krogan NJ, Geschwind DH, Gan L
JournalCell
Volume185
Issue4
Pagination712-728.e14
Date Published2022 02 17
ISSN1097-4172
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.

DOI10.1016/j.cell.2021.12.041
Alternate JournalCell
PubMed ID35063084
PubMed Central IDPMC8857049
Grant ListU54 NS100717 / NS / NINDS NIH HHS / United States
R25 NS065723 / NS / NINDS NIH HHS / United States
K01 AG057862 / AG / NIA NIH HHS / United States
R01 AG054214 / AG / NIA NIH HHS / United States
U24 NS072026 / NS / NINDS NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States