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

Author

Listed:
  • 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
    Maastricht University)

  • Yaron Fuchs

    (Technion Israel Institute of Technology
    Augmanity)

  • Michael H. Glickman

    (Technion Israel Institute of Technology)

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.

Suggested Citation

  • 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 Koi, 2023. "Altered ubiquitin signaling induces Alzheimer’s disease-like hallmarks in a three-dimensional human neural cell culture model," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41545-7
    DOI: 10.1038/s41467-023-41545-7
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    References listed on IDEAS

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    3. Yang Shi & Kaoru Yamada & Shane Antony Liddelow & Scott T. Smith & Lingzhi Zhao & Wenjie Luo & Richard M. Tsai & Salvatore Spina & Lea T. Grinberg & Julio C. Rojas & Gilbert Gallardo & Kairuo Wang & J, 2017. "ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy," Nature, Nature, vol. 549(7673), pages 523-527, September.
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