Header

UZH-Logo

Maintenance Infos

Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts


György, Bence; Cruz, Lilian; Yellen, David; Aufiero, Massimo; Alland, Isabel; Zhang, Xuan; Ericsson, Maria; Fraefel, Cornel; Li, Yu-Ching; Takeda, Shuko; Hyman, Bradley T; Breakefield, Xandra O (2018). Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts. Scientific Reports, 8(1):2324.

Abstract

Most cases of early onset torsion dystonia (DYT1) are caused by a 3-base pair deletion in one allele of the TOR1A gene causing loss of a glutamate in torsinA, a luminal protein in the nuclear envelope. This dominantly inherited neurologic disease has reduced penetrance and no other medical manifestations. It has been challenging to understand the neuronal abnormalities as cells and mouse models which are heterozygous (Het) for the mutant allele are quite similar to wild-type (WT) controls. Here we found that patient fibroblasts and mouse neurons Het for this mutation showed significant differences from WT cells in several parameters revealed by infection with herpes simplex virus type 1 (HSV) which replicates in the nucleus and egresses out through the nuclear envelope. Using a red fluorescent protein capsid to monitor HSV infection, patient fibroblasts showed decreased viral plaque formation as compared to controls. Mouse Het neurons had a decrease in cytoplasmic, but not nuclear HSV fluorescence, and reduced numbers of capsids entering axons as compared to infected WT neurons. These findings point to altered dynamics of the nuclear envelope in cells with the patient genotype, which can provide assays to screen for therapeutic agents that can normalize these cells.

Abstract

Most cases of early onset torsion dystonia (DYT1) are caused by a 3-base pair deletion in one allele of the TOR1A gene causing loss of a glutamate in torsinA, a luminal protein in the nuclear envelope. This dominantly inherited neurologic disease has reduced penetrance and no other medical manifestations. It has been challenging to understand the neuronal abnormalities as cells and mouse models which are heterozygous (Het) for the mutant allele are quite similar to wild-type (WT) controls. Here we found that patient fibroblasts and mouse neurons Het for this mutation showed significant differences from WT cells in several parameters revealed by infection with herpes simplex virus type 1 (HSV) which replicates in the nucleus and egresses out through the nuclear envelope. Using a red fluorescent protein capsid to monitor HSV infection, patient fibroblasts showed decreased viral plaque formation as compared to controls. Mouse Het neurons had a decrease in cytoplasmic, but not nuclear HSV fluorescence, and reduced numbers of capsids entering axons as compared to infected WT neurons. These findings point to altered dynamics of the nuclear envelope in cells with the patient genotype, which can provide assays to screen for therapeutic agents that can normalize these cells.

Statistics

Citations

Dimensions.ai Metrics
5 citations in Web of Science®
4 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

39 downloads since deposited on 27 Feb 2018
12 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Virology
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Health Sciences > Multidisciplinary
Language:English
Date:1 February 2018
Deposited On:27 Feb 2018 10:01
Last Modified:08 Apr 2020 23:10
Publisher:Nature Publishing Group
ISSN:2045-2322
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41598-018-19865-2
PubMed ID:29396398

Download

Gold Open Access

Download PDF  'Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts'.
Preview
Content: Published Version
Language: English
Filetype: PDF
Size: 2MB
View at publisher
Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)