title: Chronic cerebral hypoperfusion in rats causes proteasome dysfunction and aggregation of ubiquitinated proteins.
abstract: The deposition of abnormal protein aggregates is a feature of several neurodegenerative diseases. We have employed a rat model to investigate whether chronic cerebral hypoperfusion (CCH) induces proteasome dysfunction and the accumulation of ubiquitinated proteins and aggregates in the CNS. Protein aggregation was analyzed by ethanolic phosphotungstic acid (EPTA) electron microscopy (EM), immunogold EM, laser-scanning confocal microscopy, and Western blotting. Proteasome peptidase activity was studied by peptidase activity assays. EPTA EM and immunogold EM revealed that CCH led to the accumulation of protein aggregates in rat hippocampal CA1 neurons. High-resolution confocal microscopy demonstrated the presence of ubiquitin-positive protein aggregates surrounding nuclei and along dendrites. Western blotting revealed that levels of free ubiquitin were significantly reduced and that levels of ubiquitinated proteins were markedly increased in the hippocampus of CCH rats. Direct activity measurements revealed that proteasome peptidase activity in the hippocampal region of rats was decreased after CCH induction. These data suggest that reduced proteasome activity following CCH could impair the removal of abnormally folded proteins via the ubiquitin-proteasome pathway, leading to the accumulation of potentially toxic protein aggregates that could contribute to neurodegeneration.
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji University, Shanghai 200065, China. haijiandoc@yahoo.com.cn
authors.forename: Jian
authors.initials: J
authors.lastname: Hai
authors.forename: Qi
authors.initials: Q
authors.lastname: Lin
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Su
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Jue-Feng
authors.initials: JF
authors.lastname: Wan
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000098:blood supply* / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D057149:Ubiquitinated Proteins / Q000378:metabolism*
chemical_list: D057149:Ubiquitinated Proteins; D046988:Proteasome Endopeptidase Complex