Dysfunction of Membrane Trafficking Leads to Ischemia-Reperfusion Injury After Transient Cerebral Ischemia

Abstract

Neurons require an extraordinarily high level of membrane trafficking activities because of enriched axonal terminals and dendritic branches. For that reason, defects in the membrane trafficking pathway are a hallmark of most, and may be all, neurodegenerative disorders. A major cellular membrane trafficking pathway is the Golgi apparatus (Golgi hereafter)-late endosome-lysosome axis for supplying lysosomal enzymes. This pathway is regulated by N-ethylmaleimide-sensitive factor (NSF) ATPase. This review article is to discuss a novel hypothesis that brain ischemia inactivates NSF ATPase, resulting in a cascade of events of disruption of the Golgi-endosome-lysosome pathway, release of cathepsin B (CTSB), and induction of mitochondrial outer membrane permeabilization (MOMP) during the postischemic phase. This hypothesis is supported by recent studies demonstrating that NSF is trapped into inactive protein aggregates in neurons destined to die after brain ischemia. Consequently, Golgi, transport vesicles (TVs), and late endosomes (LEs) are accumulated and damaged, which is followed by CTSB release from these damaged structures. Moderate release of CTSB cleaves Bax-like BH3 protein (Bid) to become active truncated Bid (tBid). Active tBid is then translocated to the mitochondrial outer membrane, resulting in oligomerization of BCL2-associated X protein (Bax) forming the mitochondrial outer membrane pores, and releasing mitochondrial intramembranous proteins. Extensive CTSB release, however, can digest cellular proteins indiscriminately to induce cell death. Based on these new observations, we propose a novel hypothesis, i.e., brain ischemia leads to NSF inactivation, resulting in a massive buildup of damaged Golgi, TVs and LEs, fatal release of CTSB, induction of MOMP, and eventually brain ischemia-reperfusion injury.

Quantitative proteomics reveal the alterations in the spinal�cord after myocardial ischemia‑reperfusion injury in rats

“…cerebral ischemia induced a cascade of events that may disrupt membrane trafficking pathways including Golgi apparatus-late endosome-lysosome axis, which are important for supplying lysosomal enzymes for cellular apoptosis and autophagy processes (56). Massive buildup of damaged Golgi, transport vesicles and late endosomes takes place over time in neurons destined to die after transient cerebral ischemia or cardiac arrest (57,58).…”

“…Htt functions as a scaffold for selective macroautophagy (60) and was found to be degraded after ischemic injury, it interacts with Sh3gl3 to function in microtubule-based endocytotic processes (61,62). Additionally, cerebral ischemia was reported to induce mitochondrial membrane permeabilization (56). The present study identified an upregulated protein Spg7, with proteolytic activity involved in the formation and regulation of the mitochondrial permeability transition pore, which was also reported to be regulated during cerebral ischemic injury and treatment (63), and the abnormal expression of which could cause paraplegias (64).…”

Mechanisms of AMPA Receptor Endosomal Sorting

“…There is significant overlap between endo-lysosomal, autophagosomal and ubiquitin-mediated degradation (Korolchuk et al, 2010; Cohen-Kaplan et al, 2016) and the dysregulation of these systems has been consistently observed in neurodegenerative diseases (Nedelsky et al, 2008; Lee et al, 2013). Indeed, endosomal dysfunction is an early indicator for a number of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD; Schreij et al, 2016), Niemann-Pick type C1 (D’Arcangelo et al, 2011; Rabenstein et al, 2017), and other neuropathologies, such as ischemia (Yuan et al, 2018). Crucially, these endosomal deficits result in aberrant lysosomal targeting of crucial synaptic proteins, such as AMPARs, and is thought to underlie the impairments in learning and memory seen in these pathologies.…”

The Protein Modification and Degradation Pathways after Brain Ischemia

“…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.…”

“…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.…”