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.
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Abbreviations
- NSF:
-
N-ethylmaleimide-sensitive factor ATPase
- E329Q:
-
A NSF-deficient mutant
- SNAREs:
-
Soluble NSF attachment protein receptors
- SNAP:
-
Soluble NSF attachment protein
- CTSB:
-
Cathepsin B
- CTSD:
-
Cathepsin D
- TVs:
-
Transport vesicles
- LE:
-
Late endosome
- EL:
-
Endolysosome
- L:
-
Lysosome
- MOMP:
-
Mitochondrial outer membrane permeabilization
- Bax:
-
BCL2-associated X protein
- Bid:
-
Bax-like BH3 protein
- CytC:
-
Cytochrome C
- AIF:
-
Apoptosis inducing factor
- EndoG:
-
Endonuclease G
- Htra2:
-
A mitochondrial protease
- IRI:
-
Ischemia-reperfusion injury
- Tg:
-
Transgenic
- DG:
-
Dentate gyrus
- EM:
-
Electron microscopy
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Funding
This work was supported by National Institutes of Health (NIH) grants: NS36810, NS40407, and NS097875; by Veteran Affair Merit grant: I01BX001696; and by American Heart Association 0940042N-5 to B.R.H.
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This article does not contain any studies with human subjects. All the experimental procedures involving using animals were approved by the Animal Use and Care Committee in the University of Maryland School of Medicine.
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Yuan, D., Liu, C. & Hu, B. Dysfunction of Membrane Trafficking Leads to Ischemia-Reperfusion Injury After Transient Cerebral Ischemia. Transl. Stroke Res. 9, 215–222 (2018). https://doi.org/10.1007/s12975-017-0572-0
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DOI: https://doi.org/10.1007/s12975-017-0572-0