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Immunohistochemical Analysis of the Ubiquitin Proteasome System and Autophagy Lysosome System Induced After Traumatic Intracranial Injury: Association With Time Between the Injury and Death

Sakai, Kentaro MD, PhD*; Fukuda, Takahiro MD, PhD; Iwadate, Kimiharu MD, PhD*

The American Journal of Forensic Medicine and Pathology: March 2014 - Volume 35 - Issue 1 - p 38–44
doi: 10.1097/PAF.0000000000000067
Original Articles

This study aimed to analyze how the ubiquitin proteasome system (UPS) or autophagy lysosome system (autophagy) are induced in brain tissues at different intervals after traumatic intracranial injury in humans. Injured cerebral cortices of 36 forensic autopsy cases were analyzed by immunohistochemistry using antibodies as the UPS marker (ubiquitin and lysine 48-linked polyubiquitin chains [K48]) and autophagy marker (lysine 63-linked polyubiquitin chains [K63], p62/sequestome 1 and microtubule-associated protein 1 light chain 3 [LC3]). The number of neurons and glial cells with cytoplasmic inclusions that stained positive for ubiquitin, K48, and p62 began to increase within 1 hour after intracranial injury, particularly at contusion sites. From 3.5 hours onward, an increase in cytoplasmic inclusions that stained positive for K63 and LC3 began to be detected. LC3-positive cytoplasmic inclusions were not identified after 37 days; however, the increased immunoreactivity to ubiquitin and anti-K48 antibody was maintained for 7 months. These results suggest that the UPS is activated earlier and lasts longer than autophagy, that autophagy is activated for a relatively short term (between a few hours and approximately 1 month), and that the activation occurs especially in severely damaged brain tissues following head trauma in humans.

From the Department of *Forensic Medicine and †Division of Neuropathology, Department of Neuroscience, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan.

Manuscript received April 24, 2013; accepted June 4, 2013.

This article complies with the current law of Japan.

The authors report no conflicts of interest.

Reprints: Kentaro Sakai, MD, PhD, Department of Forensic Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan. E-mail:

© 2014 by Lippincott Williams & Wilkins.