title: Phospho-beta-catenin accumulation in Alzheimer's disease and in aggresomes attributable to proteasome dysfunction.
abstract: Accumulation of cytoplasmic inclusion bodies in many neurodegenerative diseases, including Alzheimer's disease (AD), might result from dysfunction of the ubiquitin-proteasome system. This system degrades many cellular proteins, including beta-catenin, a member of the Wnt signaling pathway, and a presenilin-1-interacting protein. Phosphorylation of beta-catenin marks it for ubiquitination and rapid proteasomal degradation. We found phospho-beta-catenin accumulated as detergent-insoluble, punctate, cytoplasmic inclusions in hippocampal pyramidal neurons more abundantly in AD than in aged controls. In AD, beta-catenin was ubiquitin conjugated, thus suggesting impaired proteasome-dependent degradation. Phospho-beta-catenin was partially sequestered within granulovacuolar degeneration bodies but not in lysosomes, indicating sequestration within autophagosomes. Exposure of neuronal cultures to proteasome inhibitors induced formation of detergent-insoluble, phospho-beta-catenin-positive cytoplasmic inclusions that coalesced into aggresomes and colocalized with gamma-tubulin and vimentin. These aggregates were associated with apoptotic cell death and with activation of caspase-3, c-Jun-N-terminal kinases, and c-Jun. These findings suggest that phospho-beta-catenin accumulation in AD might result from impaired proteasome function.
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Mahin
authors.initials: M
authors.lastname: Ghanevati
authors.forename: Carol A
authors.initials: CA
authors.lastname: Miller
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D061988:Proteasome Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D051176:beta Catenin; D048031:JNK Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D046988:Proteasome Endopeptidase Complex