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 Martin; Yungui Zhou; Wenjie Luo; John Q Trojanowski; Virginia M Y Lee; Shiaoching Gong; Giovanni Manfredi; Giovanni Coppola; Nevan J Krogan; Daniel H Geschwind; Li Gan

doi:10.1016/j.cell.2021.12.041

Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration

Cell. 2022 Feb 17;185(4):712-728.e14. doi: 10.1016/j.cell.2021.12.041. Epub 2022 Jan 20.

Authors

Tara E Tracy¹, Jesus Madero-Pérez², Danielle L Swaney³, Timothy S Chang⁴, Michelle Moritz⁵, Csaba Konrad⁶, Michael E Ward⁷, Erica Stevenson⁸, Ruth Hüttenhain⁸, Grant Kauwe⁹, Maria Mercedes¹⁰, Lauren Sweetland-Martin¹⁰, Xu Chen⁷, Sue-Ann Mok¹¹, Man Ying Wong¹⁰, Maria Telpoukhovskaia⁷, Sang-Won Min⁷, Chao Wang⁷, Peter Dongmin Sohn⁷, Jordie Martin⁷, Yungui Zhou⁷, Wenjie Luo¹⁰, John Q Trojanowski¹², Virginia M Y Lee¹², Shiaoching Gong¹⁰, Giovanni Manfredi⁶, Giovanni Coppola¹³, Nevan J Krogan⁸, Daniel H Geschwind¹⁴, Li Gan¹⁵

Affiliations

¹ Gladstone Institutes, San Francisco, CA 94158, USA; Buck Institute for Research on Aging, Novato, CA 94945, USA. Electronic address: ttracy@buckinstitute.org.
² Helen and Robert Appel Alzheimer Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: jem4002@med.cornell.edu.
³ Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: danielle.swaney@gladstone.ucsf.edu.
⁴ Department of Neurology, Movement Disorders Program and Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁵ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
⁶ Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
⁷ Gladstone Institutes, San Francisco, CA 94158, USA.
⁸ Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA.
⁹ Buck Institute for Research on Aging, Novato, CA 94945, USA.
¹⁰ Helen and Robert Appel Alzheimer Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA.
¹¹ Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2R3, Canada.
¹² Center for Neurodegenerative Disease Research, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹³ Department of Neurology, Movement Disorders Program and Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
¹⁴ Department of Neurology, Movement Disorders Program and Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁵ Helen and Robert Appel Alzheimer Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: lig2033@med.cornell.edu.

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.

Keywords: APEX; Tau; Tau secretion; affinity purification mass spectrometry; interactome; mitochondria; neurodegeneration; protein-protein interaction; synapse; tauopathies.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics
Amino Acids / metabolism
Biotinylation
Brain / metabolism
Brain / pathology
Cell Nucleus / metabolism
Disease Progression
Energy Metabolism
Frontotemporal Dementia / genetics
Humans
Induced Pluripotent Stem Cells / metabolism
Mitochondria / metabolism*
Mutant Proteins / metabolism
Mutation / genetics
Nerve Degeneration / metabolism*
Nerve Degeneration / pathology
Neurons / metabolism
Protein Binding
Protein Domains
Protein Interaction Maps*
Proteomics
Severity of Illness Index
Subcellular Fractions / metabolism
Synapses / metabolism*
Tauopathies / genetics
tau Proteins / chemistry
tau Proteins / metabolism*

Substances

Amino Acids
Mutant Proteins
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding