The Protein Modification and Degradation Pathways after Brain Ischemia

Abstract

This Special Issue of Translational Stroke Research is focused on the protein modification and degradation pathways after brain ischemia and is a continuation of a previous special issue in this journal entitled: BThe protein degradation pathways after brain ischemia^ [1]. Articles in this current issue summarize recent developments and understanding of protein aggregation, modification, and degradation triggered by ischemic insult. This Special Issue seeks to reiterate that disruption in cellular protein metabolism remains an important aspect of ischemic brain injury and that mechanisms of acute neuronal cell death are closely related to those of neurodegenerative disease.Few neurological conditions are as complex and devastating as ischemia-induced brain damage. Since metabolic processes are controlled and regulated by enzymes, disturbances in protein activity regulation and turnover significantly contribute to the underlying pathophysiologic mechanisms. Ischemic insult affects all cell types and practically every aspect of cellular metabolism. Therefore, the complex response of cells to ischemic insult cannot be explained by a single pathway or mechanism. However, this is an unresolved issue since changes in protein modification and cellular signaling pathways after brain ischemia still remains poorly understood. While brain ischemia certainly results in multiple disruptions of cellular metabolic pathways, some may have a more significant impact on cell fate than others. To survive this pathologic environment, post-ischemic neurons must cope with repair and eliminate irreversibly damaged organelles and toxic materials by upregulation of cellular defense systems.This special issue of Translational Stroke Research is focused on alterations in protein metabolism, degradation mechanisms, and post-translational modifications following brain ischemic insult. Each individual article highlights and discusses a specific issue related to the topic of post-ischemic alterations in cellular protein metabolism and its contribution to ischemic cell death.Hu and colleagues discuss the pathophysiology of dysfunctional membrane trafficking mechanisms in neurons [2]. The authors hypothesize that dysfunction of a master protein that regulates membrane trafficking, N-ethylmaleimide sensitive factor (NSF) ATPase, is a major reason leading to downstream pathophysiology of intracellular organelles interactions with Golgi fragmentation and late lysosomal damage. Following ischemia, NSF is deposited into the protein aggregates leading to its inactivation. This results in a cascade of events associated with disruption of the Golgi-endosome-lysosome pathway, release of cathepsin B (CTSB), and induction of mitochondrial outer membrane permeabilization [2]. Thus, this novel hypothesis suggests that NSF inactivation triggers massive release of CTSB leading to dysfunctional mitochondria and ultimately cell death. In the next article, Dong and colleagues present data that show a massive buildup of lateendosomes and fatal release of cathepsin...

Post-Translational Modification Networks of Contractile and Cellular Stress Response Proteins in Bladder Ischemia

“…Recent studies have suggested that ischemia may be a key factor in provoking post-translational protein modifications in a variety of cells [ 23 , 24 ]. The mechanism appears to involve noxious free radicals in the ischemic cells that initiate modifications of the translated protein by adding or removing modified groups to the amino acid residues [ 25 ].…”

Differential Post-Translational Modifications of Proteins in Bladder Ischemia

“…It has been shown that ischemia may be a key player in provoking PTMs in a variety of cells [56][57][58][59][60][61][62][63]. The process of PTMs in ischemia appears to involve oxidative insult resulting from excessive production of free radicals in the ischemic cells [56][57][58][59][60][61][62].…”

“…It has been shown that ischemia may be a key player in provoking PTMs in a variety of cells [56][57][58][59][60][61][62][63]. The process of PTMs in ischemia appears to involve oxidative insult resulting from excessive production of free radicals in the ischemic cells [56][57][58][59][60][61][62]. The accumulation of free radicals instigates modification of the translated protein by inserting or detaching modified groups from the amino acid residues [56][57][58][59][60][61][62].…”

“…The process of PTMs in ischemia appears to involve oxidative insult resulting from excessive production of free radicals in the ischemic cells [56][57][58][59][60][61][62]. The accumulation of free radicals instigates modification of the translated protein by inserting or detaching modified groups from the amino acid residues [56][57][58][59][60][61][62]. Oxidative insults mediated by free radicals in the ischemic tissues were shown to modify the fibrinogen molecule and provoke inflammatory responses [59].…”

YTHDC1 mitigates ischemic stroke by promoting Akt phosphorylation through destabilizing PTEN mRNA

“…Many biochemical and molecular events including glutamate excitotoxicity, oxidative stress, apoptosis, and inflammation have been identified to be involved in the ischemic neuronal injury 1,2 . These events are intricately regulated in the transcriptional, post-transcriptional, and post-translational levels [3][4][5] . In the past few decades, hundreds of agents targeting the above pathophysiological mechanisms of acute ischemic stroke have failed in clinical trials 6,7 .…”