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

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...

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Autores principales:	Bence György, Lilian Cruz, David Yellen, Massimo Aufiero, Isabel Alland, Xuan Zhang, Maria Ericsson, Cornel Fraefel, Yu-Ching Li, Shuko Takeda, Bradley T. Hyman, Xandra O. Breakefield
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4131676be5884f5cbf65ea417d647cbb
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spelling	oai:doaj.org-article:4131676be5884f5cbf65ea417d647cbb2021-12-02T15:07:52ZMutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts10.1038/s41598-018-19865-22045-2322https://doaj.org/article/4131676be5884f5cbf65ea417d647cbb2018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-19865-2https://doaj.org/toc/2045-2322Abstract 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.Bence GyörgyLilian CruzDavid YellenMassimo AufieroIsabel AllandXuan ZhangMaria EricssonCornel FraefelYu-Ching LiShuko TakedaBradley T. HymanXandra O. BreakefieldNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bence György Lilian Cruz David Yellen Massimo Aufiero Isabel Alland Xuan Zhang Maria Ericsson Cornel Fraefel Yu-Ching Li Shuko Takeda Bradley T. Hyman Xandra O. Breakefield Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts
description	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.
format	article
author	Bence György Lilian Cruz David Yellen Massimo Aufiero Isabel Alland Xuan Zhang Maria Ericsson Cornel Fraefel Yu-Ching Li Shuko Takeda Bradley T. Hyman Xandra O. Breakefield
author_facet	Bence György Lilian Cruz David Yellen Massimo Aufiero Isabel Alland Xuan Zhang Maria Ericsson Cornel Fraefel Yu-Ching Li Shuko Takeda Bradley T. Hyman Xandra O. Breakefield
author_sort	Bence György
title	Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts
title_short	Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts
title_full	Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts
title_fullStr	Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts
title_full_unstemmed	Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts
title_sort	mutant torsina in the heterozygous dyt1 state compromises hsv propagation in infected neurons and fibroblasts
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/4131676be5884f5cbf65ea417d647cbb
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Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts

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