Borna Disease Virus Persistent Infection Activates Mitogen-activated Protein Kinase and Blocks Neuronal Differentiation of PC12 Cells

Aymeric Hans, Sylvie Syan, Claudia Crosio, Paolo Sassone-Corsi, Michel Brahic, Daniel Gonzalez-Dunia
2000 Journal of Biological Chemistry  
Persistence of Borna disease virus (BDV) in the central nervous system causes damage to specific neuronal populations. BDV is noncytopathic, and the mechanisms underlying neuronal pathology are not well understood. One hypothesis is that infection affects the response of neurons to factors that are crucial for their proliferation, differentiation, or survival. To test this hypothesis, we analyzed the response of PC12 cells persistently infected with BDV to the neurotrophin nerve growth factor
more » ... GF). PC12 is a neural crest-derived cell line that exhibits features of neuronal differentiation in response to NGF. We report that persistence of BDV led to a progressive change of phenotype of PC12 cells and blocked neurite outgrowth in response to NGF. Infection downregulated the expression of synaptophysin and growthassociated protein-43, two molecules involved in neuronal plasticity, as well as the expression of the chromaffin-specific gene tyrosine hydroxylase. We showed that the block in response to NGF was due in part to the down-regulation of NGF receptors. Moreover, although BDV caused constitutive activation of the ERK1/2 pathway, activated ERKs were not translocated to the nucleus efficiently. These observations may account for the absence of neuronal differentiation of persistently infected PC12 cells treated with NGF. Borna disease virus (BDV) 1 is a nonsegmented, negative stranded RNA virus (1, 2), belonging to the Bornaviridae family in the Mononegavirales order. BDV causes central nervous system diseases characterized by behavioral abnormalities in a wide variety of animals (3). There is evidence that BDV infects humans, although its role in neuropsychiatric disorders re-
doi:10.1074/jbc.m005107200 pmid:11073944 fatcat:fohwdhpf65gpbawmfnod57jk2y