Up-regulation of pro-nerve growth factor, neurotrophin receptor p75, and sortilin is associated with retrovirus-induced spongiform encephalomyelopathy

The progressive spongiform encephalomyelopathy caused by ts1, a neuropathogenic temperature-sensitive mutant of Moloney murine leukemia virus (MoMuLV-ts1), results in motor neuronal loss without direct neuronal infection. We have previously reported that ts1-mediated neuronal degeneration in mice has a multifactorial pathogenesis. Here, we report that in the ts1-infected central nervous system (CNS) activated neural cells showed intense immunoreactivity for pro-nerve growth factor (proNGF), neurotrophin receptor p75 (p75NTR), and sortilin in the areas showing spongiform changes. Since recent studies suggested that proNGF is more active than mature NGF in inducing neuronal death after binding to co-receptors p75NTR/sortilin, we hypothesized that overexpression of proNGF, sortilin and p75NTR play a role in ts1-induced neurodegeneration. We found that proNGF and p75NTR, but not sortilin, mRNA and protein were significantly elevated in ts1-infected brainstem compared to non-infected control tissue. There was extensive tyrosine phosphorylation of p75NTR, a marker for its activation, in ts1-infected brainstem with abundance in degenerating neurons. We explored whether the increase in the in vivo proNGF expression also occurs in cultured immortalized C1 astrocytes infected by ts1 virus. The proNGF level was significantly increased in infected C1 cells compared to control cells only after addition of fibroblast growth factor (FGF-1). We also showed increased expression of FGF-1 in the CNS of ts1-infected mice. Our findings suggest that the FGF-1 signaling pathway may be responsible for the overexpression of proNGF in neural cells during pathogenesis of ts1-induced neurodegeneration. This study provides new in vivo insights into the possible role of proNGF and its receptors in ts1-induced neurodegeneration.