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PLoS Pathog. 2015 Apr 29;11(4):e1004859. doi: 10.1371/journal.ppat.1004859. eCollection 2015 Apr.

Borna disease virus phosphoprotein impairs the developmental program controlling neurogenesis and reduces human GABAergic neurogenesis.

Author information

1
INRA, UMR 1161, Maisons-Alfort, France; ANSES, UMR Virologie, Maisons-Alfort, France; Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UMR Virologie, Maisons-Alfort, France.
2
Institut National de la Santé et de la Recherche Médicale, UMR 1043, Toulouse, France; Centre National de la Recherche Scientifique, UMR 5282, Toulouse, France; Université Paul Sabatier, Toulouse 3, Toulouse, France.
3
CECS, I-STEM, AFM, Evry, France.
4
Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UMR Virologie, Maisons-Alfort, France; Pasteur Institute, Pathogen Discovery Laboratory, Biology of Infection Unit, INSERM U1117, Paris, France.

Abstract

It is well established that persistent viral infection may impair cellular function of specialized cells without overt damage. This concept, when applied to neurotropic viruses, may help to understand certain neurologic and neuropsychiatric diseases. Borna disease virus (BDV) is an excellent example of a persistent virus that targets the brain, impairs neural functions without cell lysis, and ultimately results in neurobehavioral disturbances. Recently, we have shown that BDV infects human neural progenitor cells (hNPCs) and impairs neurogenesis, revealing a new mechanism by which BDV may interfere with brain function. Here, we sought to identify the viral proteins and molecular pathways that are involved. Using lentiviral vectors for expression of the bdv-p and bdv-x viral genes, we demonstrate that the phosphoprotein P, but not the X protein, diminishes human neurogenesis and, more particularly, GABAergic neurogenesis. We further reveal a decrease in pro-neuronal factors known to be involved in neuronal differentiation (ApoE, Noggin, TH and Scg10/Stathmin2), demonstrating that cellular dysfunction is associated with impairment of specific components of the molecular program that controls neurogenesis. Our findings thus provide the first evidence that a viral protein impairs GABAergic human neurogenesis, a process that is dysregulated in several neuropsychiatric disorders. They improve our understanding of the mechanisms by which a persistent virus may interfere with brain development and function in the adult.

PMID:
25923687
PMCID:
PMC4414417
DOI:
10.1371/journal.ppat.1004859
[Indexed for MEDLINE]
Free PMC Article

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