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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Apolipoproteins E / antagonists & inhibitors
  • Apolipoproteins E / metabolism
  • Biomarkers / chemistry
  • Biomarkers / metabolism
  • Borna Disease / metabolism
  • Borna Disease / pathology
  • Borna Disease / virology
  • Borna disease virus / physiology*
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Down-Regulation*
  • France
  • GABAergic Neurons / cytology
  • GABAergic Neurons / metabolism*
  • GABAergic Neurons / pathology
  • GABAergic Neurons / virology
  • Host-Pathogen Interactions*
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism
  • Human Embryonic Stem Cells / pathology
  • Human Embryonic Stem Cells / virology
  • Humans
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / metabolism
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / toxicity
  • Stathmin
  • Tyrosine 3-Monooxygenase / antagonists & inhibitors
  • Tyrosine 3-Monooxygenase / metabolism
  • Viral Structural Proteins / genetics
  • Viral Structural Proteins / metabolism*

Substances

  • Apolipoproteins E
  • Biomarkers
  • Carrier Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • P protein, Borna disease virus
  • Phosphoproteins
  • Recombinant Proteins
  • STMN2 protein, human
  • Stathmin
  • Viral Structural Proteins
  • noggin protein
  • Tyrosine 3-Monooxygenase

Grant support

This study was financially supported by the French National Institute for Agricultural Research (INRA). CS was financially supported by INRA, the French Ministery of Agriculture and the Paris-Ile-de-France Cluster of Life and Environmental Sciences and Technologies (Pôle STVE) and the French Agency for Food, Environmental and Occupational Health and Safety (ANSES). AH was financially supported by a grant from Région Ile-de-France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.