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Mistranslation-associated perturbations of proteostasis do not promote accumulation of amyloid beta and plaque deposition in aged mouse brain


Santhosh Kumar, Harshitha; Moore, James; Steiner, Adrian C; Sotirakis, Emmanuel; Schärli, Benjamin; Isnard-Petit, Patricia; Thiam, Kader; Wolfer, David P; Böttger, Erik C (2023). Mistranslation-associated perturbations of proteostasis do not promote accumulation of amyloid beta and plaque deposition in aged mouse brain. Cellular and Molecular Life Sciences, 80(12):378.

Abstract

A common perception in age-related neurodegenerative diseases posits that a decline in proteostasis is key to the accumulation of neuropathogenic proteins, such as amyloid beta (Aβ), and the development of sporadic Alzheimer's disease (AD). To experimentally challenge the role of protein homeostasis in the accumulation of Alzheimer's associated protein Aβ and levels of associated Tau phosphorylation, we disturbed proteostasis in single APP knock-in mouse models of AD building upon Rps9 D95N, a recently identified mammalian ram mutation which confers heightened levels of error-prone translation together with an increased propensity for random protein aggregation and which is associated with accelerated aging. We crossed the Rps9 D95N mutation into knock-in mice expressing humanized Aβ with different combinations of pathogenic mutations (wild-type, NL, NL-F, NL-G-F) causing a stepwise and quantifiable allele-dependent increase in the development of Aβ accumulation, levels of phosphorylated Tau, and neuropathology. Surprisingly, the misfolding-prone environment of the Rps9 D95N ram mutation did not affect Aβ accumulation and plaque formation, nor the level of phosphorylated Tau in any of the humanized APP knock-in lines. Our findings indicate that a misfolding-prone environment induced by error-prone translation with its inherent perturbations in protein homeostasis has little impact on the accumulation of pathogenic Aβ, plaque formation and associated phosphorylated Tau.

Abstract

A common perception in age-related neurodegenerative diseases posits that a decline in proteostasis is key to the accumulation of neuropathogenic proteins, such as amyloid beta (Aβ), and the development of sporadic Alzheimer's disease (AD). To experimentally challenge the role of protein homeostasis in the accumulation of Alzheimer's associated protein Aβ and levels of associated Tau phosphorylation, we disturbed proteostasis in single APP knock-in mouse models of AD building upon Rps9 D95N, a recently identified mammalian ram mutation which confers heightened levels of error-prone translation together with an increased propensity for random protein aggregation and which is associated with accelerated aging. We crossed the Rps9 D95N mutation into knock-in mice expressing humanized Aβ with different combinations of pathogenic mutations (wild-type, NL, NL-F, NL-G-F) causing a stepwise and quantifiable allele-dependent increase in the development of Aβ accumulation, levels of phosphorylated Tau, and neuropathology. Surprisingly, the misfolding-prone environment of the Rps9 D95N ram mutation did not affect Aβ accumulation and plaque formation, nor the level of phosphorylated Tau in any of the humanized APP knock-in lines. Our findings indicate that a misfolding-prone environment induced by error-prone translation with its inherent perturbations in protein homeostasis has little impact on the accumulation of pathogenic Aβ, plaque formation and associated phosphorylated Tau.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Molecular Medicine
Life Sciences > Molecular Biology
Life Sciences > Pharmacology
Life Sciences > Cellular and Molecular Neuroscience
Life Sciences > Cell Biology
Language:English
Date:27 November 2023
Deposited On:08 Dec 2023 14:03
Last Modified:30 Apr 2024 01:44
Publisher:Springer
ISSN:1420-682X
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1007/s00018-023-05031-z
PubMed ID:38010524
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)