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Journal article
Association of the Protein-Quality-Control Protein Ubiquilin-1 With Alzheimer's Disease Both in vitro and in vivo
Frontiers in neuroscience, v 16, pp 821059-821059
2022
PMID: 35401099
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Alzheimer's disease (AD) belongs to a class of diseases characterized by progressive accumulation and aggregation of pathogenic proteins, particularly Aβ proteins. Genetic analysis has identified
as an AD candidate gene. Ubiquilin-1 levels reduce with AD progression, suggesting a potential loss-of-function mechanism. The ubiquilin-1 protein is involved in protein quality control (PQC), which plays essential roles in cellular growth and normal cell function. Ubiquilin-1 regulates γ-secretase by increasing endoproteolysis of PS1, a key γ-secretase component. Presently, the effects of ubiquilin-1 on cellular physiology as well as Aβ-related events require further investigation. Here, we investigated the effects of ubiquilin-1 on cellular growth and viability in association with APP (amyloid-β protein precursor), APP processing-related β-secretase (BACE1, BACE) and γ-secretase using cell and animal-based models. We showed that loss-of-function in
suppresses human APP and human BACE phenotypes in wing veins and altered cell number and tissue compartment size in the wing. Additionally, we performed cell-based studies and showed that silencing
reduced cell viability and increased caspase-3 activity. Overexpression of
significantly reduced Aβ levels. Furthermore, pharmacological inhibition of γ-secretase increased ubiquilin-1 protein levels, suggesting a mechanism that regulates ubiquilin-1 levels which may associate with reduced Aβ reduction by inhibiting γ-secretase. Collectively, our results support not only a loss-of-function mechanism of ubiquilin-1 in association with AD, but also support the significance of targeting ubiquilin-1-mediated PQC as a potential therapeutic strategy for AD.
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Details
- Title
- Association of the Protein-Quality-Control Protein Ubiquilin-1 With Alzheimer's Disease Both in vitro and in vivo
- Creators
- Can Zhang - Drexel UniversityShivangi M Inamdar - Drexel UniversitySwathi Swaminathan - Drexel UniversityDaniel R Marenda - National Science FoundationAleister J Saunders - Drexel University
- Publication Details
- Frontiers in neuroscience, v 16, pp 821059-821059
- Publisher
- Frontiers
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000809781800001
- Scopus ID
- 2-s2.0-85128357199
- Other Identifier
- 991019173520204721
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- Web of Science research areas
- Neurosciences