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

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 m...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications Vol. 14; no. 1; pp. 5922 - 14
Main Authors: Maniv, Inbal, Sarji, Mahasen, Bdarneh, Anwar, Feldman, Alona, Ankawa, Roi, Koren, Elle, Magid-Gold, Inbar, Reis, Noa, Soteriou, Despina, Salomon-Zimri, Shiran, Lavy, Tali, Kesselman, Ellina, Koifman, Naama, Kurz, Thimo, Kleifeld, Oded, Michaelson, Daniel, van Leeuwen, Fred W., Verheijen, Bert M., Fuchs, Yaron, Glickman, Michael H.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 22.09.2023
Nature Publishing Group
Nature Portfolio
Subjects:
13/1
13/106
13/109
13/89
14/1
14/35
14/63
631/378/2611
631/45/474/582
631/80/304
82/16
82/29
82/80
Alzheimer's disease
Amyloid precursor protein
Cell culture
Frameshift mutation
Humanities and Social Sciences
multidisciplinary
Mutation
Neural stem cells
Neurodegenerative diseases
Neurons
Pathology
Peptides
Protein gene product 9.5
Proteins
Science
Science (multidisciplinary)
Tau protein
Ubiquitin
Ubiquitination
β-Amyloid
ISSN:2041-1723, 2041-1723
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Using a 3-D neural platform, the authors show that a ubiquitin variant is sufficient to induce Alzheimer’s disease-like pathology in human neurons. Suppressing expression of this variant improved pathology in neurons carrying familial mutations.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-41545-7