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 (p75(NTR)), 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 p75(NTR)/sortilin, we hypothesized that overexpression of proNGF, sortilin and p75(NTR) play a role in ts1-induced neurodegeneration. We found that proNGF and p75(NTR), 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 p75(NTR), 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.
Stoica
George
G
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 77843, USA. gstoica@cvm.tamu.edu
Lungu
Gina
G
Kim
Hun-Taek
HT
Wong
Paul K Y
PK
D033942:Adaptor Proteins, Vesicular Transport; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001921:Brain / Q000473:pathology / Q000821:virology; D002478:Cells, Cultured; D002493:Central Nervous System Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D047468:Immunoprecipitation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008979:Moloney murine leukemia virus; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D008562:Membrane Glycoproteins; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D020800:Receptor, Nerve Growth Factor; D014443:Tyrosine; D000099183:Sortilin