G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic
Author(s)
Type
Journal Article
Abstract
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a progressive neurodegenerative disease caused by point mutations in the gene for neuroserpin, a serine protease inhibitor of the nervous system. Different mutations are known that are responsible for mutant neuroserpin polymerization and accumulation as inclusion bodies in many cortical and subcortical neurons, thereby leading to cell death, dementia and epilepsy. Many efforts have been undertaken to elucidate the molecular pathways responsible for neuronal death. Most investigations have concentrated on analysis of intracellular mechanisms such as endoplasmic reticulum (ER) stress, ER-associated protein degradation (ERAD) and oxidative stress. We have generated a HEK-293 cell model of FENIB by overexpressing G392E-mutant neuroserpin and in this study we examine trafficking and toxicity of this polymerogenic variant. We observed that a small fraction of mutant neuroserpin is secreted via the ER-to-Golgi pathway, and that this release can be pharmacologically regulated. Overexpression of the mutant form of neuroserpin did not stimulate cell death in the HEK-293 cell model. Finally, when treating primary hippocampal neurons with G392E neuroserpin polymers, we did not detect cytotoxicity or synaptotoxicity. Altogether, we report here that a polymerogenic mutant form of neuroserpin is secreted from cells but is not toxic in the extracellular milieu.
Date Issued
2021-04-22
Date Acceptance
2021-04-06
Citation
Scientific Reports, 2021, 11 (1), pp.1-13
ISSN
2045-2322
Publisher
Nature Publishing Group
Start Page
1
End Page
13
Journal / Book Title
Scientific Reports
Volume
11
Issue
1
Copyright Statement
© The Author(s) 2021
License URL
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000642742500097&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
TISSUE-PLASMINOGEN ACTIVATOR
FAMILIAL ENCEPHALOPATHY
Z ALPHA(1)-ANTITRYPSIN
INHIBITOR NEUROSERPIN
MUTANT NEUROSERPIN
POLYMERS
ACCUMULATION
DYSFUNCTION
PLASTICITY
Publication Status
Published
Article Number
ARTN 8766
Date Publish Online
2021-04-22