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G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic

Title: G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic
Authors: Ingwersen, T
Linnenberg, C
D'Acunto, E
Temori, S
Paolucci, I
Wasilewski, D
Mohammadi, B
Kirchmair, J
Glen, RC
Miranda, E
Glatzel, M
Galliciotti, G
Item 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.
Issue Date: 22-Apr-2021
Date of Acceptance: 6-Apr-2021
URI: http://hdl.handle.net/10044/1/93848
DOI: 10.1038/s41598-021-88090-1
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
Keywords: 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
Animals
Endoplasmic Reticulum
Golgi Apparatus
HEK293 Cells
Heredodegenerative Disorders, Nervous System
Hippocampus
Humans
Mice
Mice, Transgenic
Mutation
Neurons
Neuropeptides
Serpins
Synapses
Hippocampus
Neurons
Synapses
Endoplasmic Reticulum
Golgi Apparatus
Animals
Mice, Transgenic
Humans
Mice
Heredodegenerative Disorders, Nervous System
Neuropeptides
Serpins
Mutation
HEK293 Cells
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
Online Publication Date: 2021-04-22
Appears in Collections:Department of Metabolism, Digestion and Reproduction



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