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Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes
Wolfe, Michael S Shi, Yigong Ackley, Brian D. Miao, Yinglong Saraf, Anita Douglas, Justin T. Bhattarai, Sanjay Overmeyer, Caitlin Noorani, Arshad Do, Hung
Wolfe, Michael S
Shi, Yigong
Ackley, Brian D.
Miao, Yinglong
Saraf, Anita
Douglas, Justin T.
Bhattarai, Sanjay
Overmeyer, Caitlin
Noorani, Arshad
Do, Hung
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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Note: This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.
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2024-03-15
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Cell Press
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proteolysis
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Devkota S, Zhou R, Nagarajan V, Maesako M, Do H, Noorani A, Overmeyer C, Bhattarai S, Douglas JT, Saraf A, Miao Y, Ackley BD, Shi Y, Wolfe MS. Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes. Cell Rep. 2024 Feb 27;43(2):113761. doi: 10.1016/j.celrep.2024.113761. Epub 2024 Feb 13. PMID: 38349793; PMCID: PMC10941010