Inefficient quality control of ribosome stalling during APP synthesis generates CAT-tailed species that precipitate hallmarks of Alzheimer’s disease

Autor: Yu Li, Ji Geng, Su Guo, Sungun Huh, Ishaq Tantray, William W. Seeley, Salvatore Spina, Charles G. Glabe, Suman Rimal, Rasika Vartak, Bingwei Lu, Shuangxi Li, Lea T. Grinberg, Hannes Vogel
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Aging
Plaque
Amyloid
Neurodegenerative
Alzheimer's Disease
Ribosome
Pathogenesis
Amyloid beta-Protein Precursor
Mice
Amyloid precursor protein
2.1 Biological and endogenous factors
Aetiology
Plaque
biology
Ribosome stalling
Translation (biology)
Cell biology
Neurological
Drosophila
Alzheimer’s disease
Amyloid
CAT-tailing
Clinical Sciences
Amyloid precursor protein C-terminal fragment (APP
Pathology and Forensic Medicine
Cellular and Molecular Neuroscience
Alzheimer Disease
mental disorders
Acquired Cognitive Impairment
Amyloid precursor protein C-terminal fragment (APP.C99)
Animals
Humans
Ribosome-associated quality control
RC346-429
Protein Processing
C99)
Mechanism (biology)
Research
Autophagy
Post-Translational
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
Brain Disorders
Amyloid precursor protein C-terminal fragment
Proteostasis
Cell culture
Protein Biosynthesis
biology.protein
Dementia
Neurology (clinical)
Biochemistry and Cell Biology
Neurology. Diseases of the nervous system
Protein Processing
Post-Translational
Ribosomes
Zdroj: Acta Neuropathologica Communications, Vol 9, Iss 1, Pp 1-24 (2021)
Acta Neuropathologica Communications
Acta neuropathologica communications, vol 9, iss 1
ISSN: 2051-5960
Popis: Amyloid precursor protein (APP) metabolism is central to Alzheimer’s disease (AD) pathogenesis, but the key etiological driver remains elusive. Recent failures of clinical trials targeting amyloid-β (Aβ) peptides, the proteolytic fragments of amyloid precursor protein (APP) that are the main component of amyloid plaques, suggest that the proteostasis-disrupting, key pathogenic species remain to be identified. Previous studies suggest that APP C-terminal fragment (APP.C99) can cause disease in an Aβ-independent manner. The mechanism of APP.C99 pathogenesis is incompletely understood. We used Drosophila models expressing APP.C99 with the native ER-targeting signal of human APP, expressing full-length human APP only, or co-expressing full-length human APP and β-secretase (BACE), to investigate mechanisms of APP.C99 pathogenesis. Key findings are validated in mammalian cell culture models, mouse 5xFAD model, and postmortem AD patient brain materials. We find that ribosomes stall at the ER membrane during co-translational translocation of APP.C99, activating ribosome-associated quality control (RQC) to resolve ribosome collision and stalled translation. Stalled APP.C99 species with C-terminal extensions (CAT-tails) resulting from inadequate RQC are prone to aggregation, causing endolysosomal and autophagy defects and seeding the aggregation of amyloid β peptides, the main component of amyloid plaques. Genetically removing stalled and CAT-tailed APP.C99 rescued proteostasis failure, endolysosomal/autophagy dysfunction, neuromuscular degeneration, and cognitive deficits in AD models. Our finding of RQC factor deposition at the core of amyloid plaques from AD brains further supports the central role of defective RQC of ribosome collision and stalled translation in AD pathogenesis. These findings demonstrate that amyloid plaque formation is the consequence and manifestation of a deeper level proteostasis failure caused by inadequate RQC of translational stalling and the resultant aberrantly modified APP.C99 species, previously unrecognized etiological drivers of AD and newly discovered therapeutic targets. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01268-6.
Databáze: OpenAIRE
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