Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration

Publication Type Academic Article
Authors Tracy TE, Madero-Pérez J, Swaney DL, Chang TS, Moritz M, Konrad C, Ward ME, Stevenson E, Hüttenhain R, Kauwe G, Mercedes M, Sweetland-Martin L, Chen X, Mok S-A, Wong MYing, Telpoukhovskaia M, Min S-W, Wang C, Sohn PD, Martin J, Zhou Y, Luo W, Trojanowski JQ, Lee VMY, Gong S, Manfredi G, Coppola G, Krogan NJ, Geschwind DH, Gan L
Journal Cell
Volume 185
Issue 4
Pagination 712-728.e14
Date Published 01/20/2022
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.

DOI 10.1016/j.cell.2021.12.041
PubMed ID 35063084
PubMed Central ID PMC8857049
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