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.
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.
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