Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts
| Autor: | Massimo Aufiero, Shuko Takeda, Bradley T. Hyman, Xandra O. Breakefield, Isabel Alland, Yu-Ching Li, Xuan Zhang, Maria Ericsson, Lilian Cruz, Bence György, Cornel Fraefel, David Yellen |
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| Přispěvatelé: | University of Zurich, Breakefield, Xandra O |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Viral Plaque Assay Cytoplasm Heterozygote Science Mutant Herpesvirus 1 Human Biology medicine.disease_cause Virus Replication Article Green fluorescent protein 03 medical and health sciences Mice medicine Animals Humans Cells Cultured Cell Nucleus Neurons Mutation 1000 Multidisciplinary Multidisciplinary Fibroblasts Molecular biology Viral plaque 3. Good health Cell nucleus 030104 developmental biology medicine.anatomical_structure Herpes simplex virus Viral replication Host-Pathogen Interactions Medicine 570 Life sciences biology Mutant Proteins 10244 Institute of Virology Molecular Chaperones |
| Zdroj: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-11 (2018) |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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