Lonskaya I, Shekoyan AR, Hebron ML, Desforges N, Algarzae NK, Moussa CE

Alzheimer's disease (AD) is an aging disorder characterized by amyloid-β (Aβ) 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 ...

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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 Aβ1-42 in the hippocampus and cortex of AD patients. Parkin accumulation with intraneuronal Aβ and p-Tau was detected in autophagosomes in AD brains. To determine the role of parkin in Aβ clearance, we generated gene transfer animals expressing lentiviral Aβ1-42 with and without parkin and examined autophagic mechanisms. Lentiviral expression of Aβ1-42 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 Aβ1-42 and p-Tau into the lysosome. Taken together, these data suggest that Aβ1-42 alters normal autophagy and parkin enhances autophagic clearance. In conclusion, decreased parkin solubility may lead to co-localization with intraneuronal Aβ1-42 and compromise the cell autophagic clearance ability. Parkin may clear autophagic defects via autophagosome degradation.

Date: Sep. 06, 2012

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