Parkin promotes intracellular Abeta1-42 clearance.
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.
Burns
Mark P
MP
Department of Neuroscience, Georgetown University School of Medicine, Washington, DC 20057, USA.
Zhang
Lihua
L
Rebeck
G William
GW
Querfurth
Henry W
HW
Moussa
Charbel E-H
CE
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex