Defective ubiquitination of cerebral proteins in Alzheimer's disease

Citation
Ml. Salon et al., Defective ubiquitination of cerebral proteins in Alzheimer's disease, J NEUROSC R, 62(2), 2000, pp. 302-310
Citations number
45
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROSCIENCE RESEARCH
ISSN journal
03604012 → ACNP
Volume
62
Issue
2
Year of publication
2000
Pages
302 - 310
Database
ISI
SICI code
0360-4012(20001015)62:2<302:DUOCPI>2.0.ZU;2-4
Abstract
Alzheimer's disease (AD) is characterized by the presence of neurofibrillar y tangles (NFT), senile plaques, and cerebrovascular deposits of amyloid-P. Ubiquitin has also been shown to be present in some of the inclusions char acteristic of this disease. To obtain further insight into the role played by the ubiquitin pathway in AD, we investigated the capacity of postmortem samples of cerebral cortex from normal and AD patients to form high-molecul ar-weight ubiquitin-protein conjugates. Activity of the ubiquitin-activatin g enzyme (El) and ubiquitin-conjugating enzymes (E2) involved in the ubiqui tin pathway was also determined. In normal samples, the amount of high-mole cular-weight ubiquitin-protein conjugates (HMW-UbPC) in cytosol increased w ith incubation time, whereas, in samples of AD cases, these were almost und etectable. The addition of an adult rat fraction, enriched in ubiquitinatin g enzymes, restored the capacity of AD brain cytosolic fraction to form con jugates. The trypsin-like proteolytic activity of the 26S proteasome was fo und to be decreased in AD cytosol brain. Assay of the activity of El and E2 by thiol-ester formation revealed a significant decrease in AD samples. Mo reover, Western blotting using a specific antibody against El showed a dram atic drop of this enzyme in the cytosolic fraction, whereas normal levels w ere found in the particulate fraction, suggesting a possible delocalization of the enzyme. Our results suggest that a failure in the ubiquitination en zymatic system in brain cytosol may contribute to fibrillar pathology in AD . (C) 2000 Wiley-Liss, Inc.