Human Molecular Genetics Advance Access originally published online on May 29, 2009
Human Molecular Genetics 2009 18(17):3206-3216; doi:10.1093/hmg/ddp258
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Parkin promotes intracellular Aβ1–42 clearance
1 Department of Neuroscience 2 Department of Biochemistry, Molecular and Cell Biology and 3 Proteomics and Metabolomics Shared Resource, Georgetown University School of Medicine, Washington DC 20057, USA 4 Department of Neurology, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA
* To whom correspondence should be addressed at: Department of Neuroscience and Department of Biochemistry, Molecular & Cell Biology, Georgetown University School of Medicine, 3970 Reservoir Rd, NW, TRB, Room WP26B, Washington DC 20057, USA. Tel: +1 2026875760; Fax: +1 2026870617; Email: cem46{at}georgetown.edu
Received May 8, 2009; Revised May 21, 2009; Accepted May 27, 2009
Alzheimer's disease and Parkinson's disease are common neurodegenerative diseases that may share some underlying mechanisms of pathogenesis. Aβ1–42 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 Aβ1–42. Lentiviral constructs encoding either human parkin or human Aβ1–42 were used to infect M17 neuroblastoma cells. Parkin expression resulted in reduction of intracellular human Aβ1–42 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 Aβ1–42 levels and Aβ1–42-induced neuronal degeneration in vivo. Parkin increased proteasomal activity, and proteasomal inhibition blocked the effects of parkin on reducing Aβ1–42 levels. Incubation of Aβ1–42 cell lysates with ubiquitin, in the presence of parkin, demonstrated the generation of Aβ–ubiquitin complexes. These data indicate that parkin promotes ubiquitination and proteasomal degradation of intracellular Aβ1–42 and demonstrate a protective effect in neurodegenerative diseases with Aβ deposits.