The role of PARL and HtrA2 in striatal neuronal injury after transient global cerebral ischemia

Hideyuki Yoshioka, Masataka Katsu, Hiroyuki Sakata, Nobuya Okami, Takuma Wakai, Hiroyuki Kinouchi, Pak H. Chan

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

The presenilin-associated rhomboid-like (PARL) protein and high temperature requirement factor A2 (HtrA2) are key regulators of mitochondrial integrity and play pivotal roles in apoptosis. However, their roles after cerebral ischemia have not been thoroughly elucidated. To clarify these roles, mice were subjected to transient global cerebral ischemia, and striatal neuronal injury was assessed. Western blot and coimmunoprecipitation analyses revealed that PARL and processed HtrA2 localized to mitochondria, and that PARL was bound to HtrA2 in sham animals. Expression of PARL and processed HtrA2 in mitochondria significantly decreased 6 to 72 hours after ischemia, and the binding of PARL to HtrA2 disappeared after ischemia. In contrast, expression of processed HtrA2 increased 24 hours after ischemia in the cytosol, where HtrA2 was bound to X chromosome-linked inhibitor-of-apoptosis protein (XIAP). Administration of PARL small interfering RNA inhibited HtrA2 processing and worsened ischemic neuronal injury. Our results show that downregulation of PARL after ischemia is a key step in ischemic neuronal injury, and that it decreases HtrA2 processing and increases neuronal vulnerability. In addition, processed HtrA2 released into the cytosol after ischemia contributes to neuronal injury via inhibition of XIAP.

Original languageEnglish
Pages (from-to)1658-1665
Number of pages8
JournalJournal of Cerebral Blood Flow and Metabolism
Volume33
Issue number11
DOIs
Publication statusPublished - 2013 Nov

Keywords

  • global cerebral ischemia
  • high temperature requirement factor A2
  • mitochondria
  • presenilin-associated rhomboid like protein
  • striatum

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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