Protection against Murine Leukemia Virus-InducedSpongiform Myeloencephalopathy in Mice Overexpressing Bcl-2 butNot in Mice Deficient for Interleukin-6, Inducible NitricOxide Synthetase, ICE, Fas, Fas Ligand, or TNF-R1Genes

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Abstract
Some murine leukemia viruses (MuLVs), among them Cas-Br-E andts-1 MuLVs, are neurovirulent, inducing spongiform myeloencephalopathy and hind limb paralysis in susceptible mice. It has been shown that theenvgene of these viruses harbors the determinant of neurovirulence. It appears that neuronal loss occurs by an indirect mechanism, since the target motor neurons have not been found to be infected. However, the pathogenesis of the disease remains unclear. Several lymphokines, cytokines, and other cellular effectors have been found to be aberrantly expressed in the brains of infected mice, but whether these are required for the development of the neurodegenerative lesions is not known. In an effort to identify the specific effectors which are indeed required for the initiation and/or development of spongiform myeloencephalopathy, we inoculated gene-deficient (knockout [KO]) mice withts-1 MuLV. We show here that interleukin-6 (IL-6), inducible nitric oxide synthetase (iNOS), ICE, Fas, Fas ligand (FasL), and TNF-R1 KO mice still develop signs of disease. However, transgenic mice overexpressing Bcl-2 in neurons (NSE/Bcl-2) were largely protected from hind limb paralysis and had less-severe spongiform lesions. These results indicate that motor neuron death occurs in this disease at least in part by a Bcl-2-inhibitable pathway not requiring the ICE, iNOS, Fas/FasL, TNF-R1, and IL-6 gene products.