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

Autor: 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
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Scientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
Druh dokumentu: article
ISSN: 2045-2322
DOI: 10.1038/s41598-018-19865-2
Popis: 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.
Databáze: Directory of Open Access Journals
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