Diminished parkin solubility and co-localization with intraneuronal amyloid-ß are associated with autophagic defects in Alzheimer's disease.
J Alzheimers Dis
; 33(1): 231-47, 2013.
Article
en En
| MEDLINE
| ID: mdl-22954671
ABSTRACT
Alzheimer's disease (AD) is an aging disorder characterized by amyloid-ß (Aß) accumulation in extracellular plaques and formation of intracellular tangles containing hyperphosphorylated tau (p-Tau). Autophagic defects, leading to accumulation of autophagosomes, are recognized in AD. Parkin is an E3 ubiquitin ligase involved in degradation of proteins via autophagy and the proteasome. We investigated the role of parkin in postmortem brain tissues from 21 AD patients and 15 control subjects. We detected decreased parkin solubility in AD cortex and parkin co-localization with intraneuronal Aß(1-42) in the hippocampus and cortex of AD patients. Parkin accumulation with intraneuronal Aß and p-Tau was detected in autophagosomes in AD brains. To determine the role of parkin in Aß clearance, we generated gene transfer animals expressing lentiviral Aß(1-42)with and without parkin and examined autophagic mechanisms. Lentiviral expression of Aß(1-42) led to p-Tau accumulation and induced autophagic defects, leading to accumulation of autophagic vacuoles. However, co-expression of wild type parkin facilitated autophagic clearance and promoted deposition of Aß(1-42) and p-Tau into the lysosome. Taken together, these data suggest that Aß(1-42) alters normal autophagy and parkin enhances autophagic clearance. In conclusion, decreased parkin solubility may lead to co-localization with intraneuronal Aß(1-42) and compromise the cell autophagic clearance ability. Parkin may clear autophagic defects via autophagosome degradation.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
/
Autofagia
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Péptidos beta-Amiloides
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Ubiquitina-Proteína Ligasas
/
Enfermedad de Alzheimer
/
Neuronas
Tipo de estudio:
Risk_factors_studies
Límite:
Aged
/
Aged80
/
Animals
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Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
J Alzheimers Dis
Asunto de la revista:
GERIATRIA
/
NEUROLOGIA
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos