The ubiquitin ligase UBE4B regulates amyloid precursor protein ubiquitination, endosomal trafficking, and amyloid ß42 generation and secretion.
Mol Cell Neurosci
; 108: 103542, 2020 10.
Article
en En
| MEDLINE
| ID: mdl-32841720
ABSTRACT
The extracellular accumulation of amyloid ß (Aß) fragments of amyloid precursor protein (APP) in brain parenchyma is a pathological hallmark of Alzheimer's disease (AD). APP can be cleaved into Aß on late endosomes/multivesicular bodies (MVBs). E3 ubiquitin ligases have been linked to Aß production, but specific E3 ligases associated with APP ubiquitination that may affect targeting of APP to endosomes have not yet been described. Using cultured cortical neurons isolated from rat pups, we reconstituted APP movement into the internal vesicles (ILVs) of MVBs. Loss of endosomal sorting complexes required for transport (ESCRT) components inhibited APP movement into ILVs and increased endosomal Aß42 generation, implying a requirement for APP ubiquitination. We identified an ESCRT-binding and APP-interacting endosomal E3 ubiquitin ligase, ubiquitination factor E4B (UBE4B) that regulates APP ubiquitination. Depleting UBE4B in neurons inhibited APP ubiquitination and internalization into MVBs, resulting in increased endosomal Aß42 levels and increased neuronal secretion of Aß42. When we examined AD brains, we found levels of the UBE4B-interacting ESCRT component, hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), were significantly decreased in AD brains. These data suggest that ESCRT components critical for membrane protein sorting in the endocytic pathway are altered in AD. These results indicate that the molecular machinery underlying endosomal trafficking of APP, including the ubiquitin ligase UBE4B, regulates Aß levels and may play an essential role in AD progression.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
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Endosomas
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Péptidos beta-Amiloides
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Ubiquitinación
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Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2020
Tipo del documento:
Article