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Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice

Abstract

Age-related neurodegenerative diseases (NDDs) are associated with the aggregation and propagation of specific pathogenic protein species (e.g., Aβ, α-synuclein). However, whether disruption of synaptic homeostasis results from protein misfolding per se rather than accumulation of a specific rogue protein is an unexplored question. Here, we show that error-prone translation, with its frequent outcome of random protein misfolding, is sufficient to recapitulate many early features of NDDs, including perturbed Ca2+ signaling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in behavioral changes reminiscent of early Alzheimer disease (AD), such as learning and memory deficits, maladaptive emotional responses, epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation, accompanied by hippocampal NPY expression and cerebral glucose hypometabolism. Collectively, our findings suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs, providing an alternative framework for understanding the initiation of AD.

Keywords: Alzheimer; CP: Neuroscience; error-prone translation; neurodegenerative diseases; pathogenesis; protein misfolding; synaptic homeostasis

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
05 Vetsuisse Faculty > Veterinary Clinic > Department of Clinical Diagnostics and Services
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > General Biochemistry, Genetics and Molecular Biology
Language:German
Date:27 September 2022
Deposited On:19 Oct 2022 11:54
Last Modified:28 Oct 2024 02:36
Publisher:Cell Press (Elsevier)
ISSN:2211-1247
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.celrep.2022.111433
PubMed ID:36170830
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  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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