Protein Misfolding, Aggregation, and Autophagy After Brain Ischemia
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REVIEW ARTICLE
Protein Misfolding, Aggregation, and Autophagy After Brain Ischemia Tianfei Luo & Yujung Park & Xin Sun & Chunli Liu & Bingren Hu
Received: 30 July 2013 / Revised: 17 October 2013 / Accepted: 20 October 2013 / Published online: 9 November 2013 # Springer Science+Business Media New York 2013
Abstract Ischemic brain injury is a common disorder linked to a variety of diseases. Significant progress has been made in our understanding of the underlying mechanisms. Previous studies show that protein misfolding, aggregation, and multiple organelle damage are major pathological events in postischemic neurons. The autophagy pathway is the chief route for bulk degradation of protein aggregates and damaged organelles. The latest studies suggest that impairment of autophagy contributes to abnormal protein aggregation and organelle damages after brain ischemia. This article reviews recent studies of protein misfolding, aggregation, and impairment of autophagy after brain ischemia.
Keywords Brain ischemia . Protein misfolding . Protein aggregation . Autophagy . Protein synthesis . Chaperone . Multiple organelle damage . Ubiquitin-proteasomal system
Abbreviations AP Autophagosome AL Autolysosome 2VO Two-vessel occlusion with hypotension ischemia model HSC70 Heat-shock cognate protein 70 HSP40 Heat-shock protein 40 ATG Autophagic gene-related protein LC3 Microtubule-associated protein light chain 3 DG Dentate gyrus ER Endoplasmic reticulum
T. Luo : Y. Park : X. Sun : C. Liu : B. Hu (*) Shock, Trauma and Anesthesiology Research Center, Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA e-mail: [email protected]
Ischemic Neuronal Injury An episode of brain ischemia leads to delayed neuronal death that takes place after several days of reperfusion following a period of ischemia [33]. Such a slowly progressing type of neuronal death is also referred to as the maturation phenomenon [31]. Delayed neuronal death also occurs in the penumbral area and is different from the cell rupture type of neuronal necrosis in the core area after focal ischemia [54]. Several lines of evidence suggest that delayed neuronal death may be different from apoptosis or programmed cell death [8, 11, 29, 45]. In rat and mouse transient brain ischemia models, delayed neuronal death occurs in all neurons at 48–72 h of reperfusion after brief episode of ischemia, but hippocampal CA1 pyramidal neurons are more sensitive to ischemia than neurons in CA3, DG, and neocortical regions. For example, 15 min of ischemia leads to delayed neuronal death in CA1 neurons but leaves most CA3, DG, and neocortical neurons largely intact in the rat two-vessel occlusion with hypotension ischemia (2VO) model (Fig. 1). Twenty minutes of ischemia also leads to delayed neuronal death in CA3, DG, and neocortical regions in this brain ischemia model [46, 47]. During the delayed period, neurons destined to die appear essentially normal under the light microscope but accumulate progressively large amounts of abnormal protein a
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