Parkin promotes intracellular A{beta}1-42 clearance.


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06-02-09 09:49 AM
Parkin promotes intracellular A{beta}1-42 clearance.
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Parkin promotes intracellular A{beta}1-42 clearance.

Hum Mol Genet. 2009 May 29;

Authors: Burns MP, Zhang L, Rebeck GW, Querfurth HW, Moussa CE

Alzheimer's disease and Parkinson's disease are common neurodegenerative diseases that may share some underlying mechanisms of pathogenesis. Abeta(1-42) fragments are found intracellularly, and extracellularly as amyloid plaques, in Alzheimer's disease and in dementia with Lewy Bodies. Parkin is an E3-ubiquitin ligase involved in proteasomal degradation of intracellular proteins. Mutations in parkin, which result in loss of parkin function, lead to early onset Parkinsonism. Here we tested whether the ubiquitin ligase activity of parkin could lead to reduction in intracellular human Abeta(1-42). Lentiviral constructs encoding either human parkin or human Abeta(1-42) were used to infect M17 neuroblastoma cells. Parkin expression resulted in reduction of intracellular human Abeta(1-42) levels and protected against its toxicity in M17 cells. Co-injection of lentiviral constructs into control rat primary motor cortex demonstrated that parkin co-expression reduced human Abeta(1-42) levels and Abeta(1-42)-induced neuronal degeneration in vivo. Parkin increased proteasomal activity, and proteasomal inhibition blocked the effects of parkin on reducing Abeta(1-42) levels. Incubation of Abeta(1-42) cell lysates with ubiquitin, in the presence of parkin, demonstrated the generation of Abeta-ubiquitin complexes. These data indicate that parkin promotes ubiquitination and proteasomal degradation of intracellular Abeta(1-42) and demonstrate a protective effect in neurodegenerative diseases with Abeta deposits.

PMID: 19483198 [PubMed - as supplied by publisher]