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(Stroke. 2007;38:3230.)
© 2007 American Heart Association, Inc.

Original Contributions

Protein Aggregation and Proteasome Dysfunction After Brain Ischemia

Pengfei Ge, MD; Yinan Luo, MD; Cindy L. Liu, MD Bingren Hu, MD, PhD

From the Department of Neurosurgery (P.G., Y.L.), First Teaching Hospital, Jilin University, Jilin, China, and the Neurochemistry Laboratory of Brain Injury and Ischemia (P.G., Y.L., C.L.L., B.H.), Department of Neurology, University of Miami School of Medicine, Miami, Fla.

Correspondence to Dr Bingren Hu, Department of Neurology, University of Miami School of Medicine, PO Box 16960, Miami, FL 33136. E-mail bhu{at}med.Miami.edu

Background and Purpose— Protein unfolding and aggregation are dominant early pathogenic events in neurons after brain ischemia. This study used a transient cerebral ischemia model to investigate whether overproduction of unfolded proteins after brain ischemia is a consequence of proteasome dysfunction.

Methods— Proteasome peptidase activity and proteasome subcellular redistribution and assembly were studied by peptidase activity assay, Western blot analysis, and size-exclusion chromatography.

Results— Proteasome peptidase activity, as determined with the peptide substrate succinyl-LLVY-7-amino-4-methylcoumarin, was moderately decreased, and the 26S proteasome was disassembled during the early period of reperfusion after transient brain ischemia. Furthermore, the proteasome subunits, particularly the 19S components, were deposited into the protein aggregate-containing fraction after an episode of transient cerebral ischemia.

Conclusions— These results clearly demonstrate that after an episode of brain ischemia, proteasomes are disassembled and aggregated and thus fail to function normally. Deposition of proteasomes into protein aggregates may also indicate that proteasomes attempt to degrade ubiquitin-conjugated proteins (ubiproteins) overproduced after brain ischemia. However, ubiproteins are too numerous to be degraded and trap some of the proteasomes into their aggregates after brain ischemia.

Key Words: brain ischemia/reperfusion • delayed neuronal death • protein aggregation • protein misfolding • proteosomes • ubiquitin • size-exclusion chromatography