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Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes
Devkota, Sujan Zhou, Rui Nagarajan, Vaishnavi Maesako, Masato Do, Hung Noorani, Arshad Overmeyer, Caitlin Bhattarai, Sanjay Douglas, Justin T. Saraf, Anita
Devkota, Sujan
Zhou, Rui
Nagarajan, Vaishnavi
Maesako, Masato
Do, Hung
Noorani, Arshad
Overmeyer, Caitlin
Bhattarai, Sanjay
Douglas, Justin T.
Saraf, Anita
Abstract
Mutations that cause familial Alzheimer’s disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide (Aβ). Nevertheless, whether Aβ is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aβ production likewise led to synaptic loss. Collectively, these findings implicate the stalled process—not the products—of γ-secretase cleavage of substrates in FAD pathogenesis.
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A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.
Date
2024-02
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Elsevier
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Sujan Devkota, Rui Zhou, Vaishnavi Nagarajan, Masato Maesako, Hung Do, Arshad Noorani, Caitlin Overmeyer, Sanjay Bhattarai, Justin T. Douglas, Anita Saraf, Yinglong Miao, Brian D. Ackley, Yigong Shi, Michael S. Wolfe, Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes,
Cell Reports, Volume 43, Issue 2, 2024, 113761, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2024.113761.