Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes
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
Affiliations
Sujan Devkota
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA
Rui Zhou
Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
Vaishnavi Nagarajan
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA
Masato Maesako
Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Hung Do
Center for Computational Biology, University of Kansas, Lawrence, KS, USA
Arshad Noorani
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA
Caitlin Overmeyer
Graduate Program in Neurosciences, University of Kansas, Lawrence, KS, USA
Sanjay Bhattarai
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA
Justin T. Douglas
Nuclear Magnetic Resonance Core Lab, University of Kansas, Lawrence, KS, USA
Anita Saraf
Mass Spectrometry and Analytical Proteomic Laboratory, University of Kansas, Lawrence, KS, USA
Yinglong Miao
Center for Computational Biology, University of Kansas, Lawrence, KS, USA; Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
Brian D. Ackley
Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
Yigong Shi
Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China; Westlake Laboratory of Life Science and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, and Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang Province, China
Michael S. Wolfe
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA; Graduate Program in Neurosciences, University of Kansas, Lawrence, KS, USA; Corresponding author
Summary: 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.
