Borna Disease Virus Phosphoprotein Impairs the Developmental Program Controlling Neurogenesis and Reduces Human GABAergic Neurogenesis

PLoS Pathogens

Alexandra Huttin¹  Daniel Gonzalez-Dunia¹  Aurélie Poulet¹  Chloé Scordel²  Alexandra Benchoua²  Marion Szelechowski²  Muriel Coulpier³  Marc Eloit⁴  Marielle Cochet-Bernoin⁴  Jennifer Richardson⁴ 

[1] ANSES, UMR Virologie, Maisons-Alfort, France;INRA, UMR 1161, Maisons-Alfort, France;Institut National de la Santé et de la Recherche Médicale, UMR 1043, Toulouse, France;Université Paris-Est, Ecole Nationale Vétérinaire d’Alfort, UMR Virologie, Maisons-Alfort, France

关键词: Neuronal differentiation;    Neurons;    Neurogenesis;    Immunostaining;    Cell differentiation;    Adult neurogenesis;    DAPI staining;    Genetic interference;   

DOI  :  10.1371/journal.ppat.1004859

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY