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

ABSTRACT: Age-related neurodegenerative diseases (NDDs) and neuronal dysfunction are associated with the aggregation and propagation of specific pathogenic protein species (e.g. Aβ, α-synuclein, tau). However, whether the 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 proteostasis dysregulation, perturbed Ca2+ signalling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in abnormal behavioral changes reminiscent of early Alzheimer's disease (AD), such as learning and memory deficits, maladaptive responses to novel stimuli, spontaneous epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation. Ectopic hippocampal NPY expression and cerebral glucose hypometabolism (18F-fluorodeoxyglucose PET) were further signs of neuronal hyperexcitability. Collectively, our findings strongly suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs providing an alternative framework for understanding the initiation of Alzheimer’s disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE193459 | GEO | 2022/09/19

REPOSITORIES: GEO

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

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