Altered ubiquitin signaling induces Alzheimer’s disease-like hallmarks in a three-dimensional human neural cell culture model

Inbal Maniv, Mahasen Sarji, Anwar Bdarneh, Alona Feldman, Roi Ankawa, Elle Koren, Inbar Magid-Gold, Noa Reis, Despina Soteriou, Shiran Salomon-Zimri, Tali Lavy, Ellina Kesselman, Naama Koifman, Thimo Kurz, Oded Kleifeld, Daniel Michaelson, Fred W. Leeuwen, Bert M. Verheijen, Yaron Fuchs () and Michael H. Glickman ()
Additional contact information
Inbal Maniv: Technion Israel Institute of Technology
Mahasen Sarji: Technion Israel Institute of Technology
Anwar Bdarneh: Technion Israel Institute of Technology
Alona Feldman: Technion Israel Institute of Technology
Roi Ankawa: Technion Israel Institute of Technology
Elle Koren: Technion Israel Institute of Technology
Inbar Magid-Gold: Technion Israel Institute of Technology
Noa Reis: Technion Israel Institute of Technology
Despina Soteriou: Technion Israel Institute of Technology
Shiran Salomon-Zimri: Tel Aviv University
Tali Lavy: Technion Israel Institute of Technology
Ellina Kesselman: The Technion Center for Electron Microscopy of Soft Matter, Technion Israel Institute of Technology
Naama Koifman: The Technion Center for Electron Microscopy of Soft Matter, Technion Israel Institute of Technology
Thimo Kurz: University of Glasgow
Oded Kleifeld: Technion Israel Institute of Technology
Daniel Michaelson: Tel Aviv University
Fred W. Leeuwen: Maastricht University
Bert M. Verheijen: Technion Israel Institute of Technology
Yaron Fuchs: Technion Israel Institute of Technology
Michael H. Glickman: Technion Israel Institute of Technology

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Alzheimer’s disease (AD) is characterized by toxic protein accumulation in the brain. Ubiquitination is essential for protein clearance in cells, making altered ubiquitin signaling crucial in AD development. A defective variant, ubiquitin B + 1 (UBB+1), created by a non-hereditary RNA frameshift mutation, is found in all AD patient brains post-mortem. We now detect UBB+1 in human brains during early AD stages. Our study employs a 3D neural culture platform derived from human neural progenitors, demonstrating that UBB+1 alone induces extracellular amyloid-β (Aβ) deposits and insoluble hyperphosphorylated tau aggregates. UBB+1 competes with ubiquitin for binding to the deubiquitinating enzyme UCHL1, leading to elevated levels of amyloid precursor protein (APP), secreted Aβ peptides, and Aβ build-up. Crucially, silencing UBB+1 expression impedes the emergence of AD hallmarks in this model system. Our findings highlight the significance of ubiquitin signalling as a variable contributing to AD pathology and present a nonclinical platform for testing potential therapeutics.

Date: 2023
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DOI: 10.1038/s41467-023-41545-7

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