Amyloid peptides in different assembly states and related effects on isolated and cellular proteasomes.
The role of amyloid-beta protein (Abeta) in the pathogenesis of Alzheimer's disease (AD) has been widely investigated and amyloid aggregates are considered a major cause of neuronal dysfunction. Increasing evidence has identified a correlation between this protein and the proteasome, the cellular proteolytic machinery, in particular the ubiquitin-proteasome system. The 20S proteasome is the catalytic core of a complex, known as 26S proteasome, and is the main responsible for the clearance of misfolded and oxidized proteins. In this work we have investigated the effects of different assembly states of two major amyloid peptides, Abeta (1-40) and Abeta (1-42) on the 20S proteasome functionality and on the ubiquitin-dependent pathway of protein degradation. In particular, we have tested proteasome activities after Abeta treatment on purified 20S complexes and on lysates of a human neuroblastoma cell line. Our findings show a significant decrease in proteasome activity, more evident in cell lysates than in isolated complexes, and an increased amount of ubiquitin-protein conjugates and of a known proteasome substrate (p27). Furthermore, the altered proteasome functionality is not associated with a decrease in cell viability, but is linked with increased levels of protein oxidation.
Cecarini
Valentina
V
Department of Molecular, Cellular and Animal Biology, University of Camerino, 62032 Camerino (MC), Italy. valentina.cecarini@unicam.it
Bonfili
Laura
L
Amici
Manila
M
Angeletti
Mauro
M
Keller
Jeffrey N
JN
Eleuteri
Anna Maria
AM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology; D014452:Ubiquitins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D014452:Ubiquitins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D046988:Proteasome Endopeptidase Complex