(1) We are investigating disease induced by Theiler’s virus (TV), a mouse picornavirus, in order to identify molecular determinants for neurovirulence and demyelination and the mechanisms involved. Certain strains from one subgroup produce a chronic persistent infection in mice in which autoimmune factors are believed to contribute to the demyelinating disease.  The demyelination caused by these strains provides one of the best experimental models for MS because of the similarity in their pathology and because the immune system appears to contribute to disease in both cases. Other strains from a second TV subgroup cause an acute, fatal polioencephalomyelitis; investigations of motor neuronal death caused by these strains as well as by poliovirus may provide a better understanding for motor neuron death in ALS.  The TV model is a valuable one for these studies because of the powerful molecular tools that are available, the interesting phenotypes of the strains, and the ease with which one can study this simple virus in a mouse.  With this goal in mind, we have produced infectious cDNA clones from strains of the two different subgroups and generated recombinant and mutated viruses. The identification of these genes may not only clarify the pathogenesis of TV disease, but also lead to an understanding of genes important in the normal CNS and in human CNS disease states (such as MS and ALS). 

(2) A main aim of our studies is the delineation of genes and gene products critical to the death and survival of neurons, especially related to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease. 
 

Weihl, C.C., Ghadge, G.D., Kennedy, S.G., Hay, N., Miller, R.J., and Roos, R.P.  Mutant presenilin-1 induced apoptosis in cultured neurons via downregulation of Akt/PKB.  J. Neurosci. 19(13):5360-5369, 1999.

Mastrianni, J.A. and Roos, R.P. The Prion Diseases. Seminars in Neurology 20 (3): 337-352, 2000.

Pallansch, M.A. and Roos, R.P. Enteroviruses: Polioviruses, Coxsackieviruses, Echoviruses, and Newer Enteroviruses.  Fields’ Virology.  (Ed. Knipe, D.N. and Howley, P.M.) 4th Edition, 2001, Vol. II pp. 725-776.

Pilipenko, E., Viktorova, E., Guest, S., Agol, V., and Roos, R.P. Cell-specific Proteins Regulate Viral RNA Translation and Virus-induced Disease. European Molecular Biology Organization Journal 20 (23): 6899-6908, 2001.

Lee, J.P., Gerin, C, Bindokas, V., Miller, R. J., Ghadge, G, and Roos, R.P. No correlation between aggregates of Cu/Zn superoxide dismutase and cell death in familial amyotrophic lateral sclerosis.  J. Neurochem.  82:1229-1238, 2002.

Roos, R.P.  Pathogenesis of Theiler’s Murine Encephalomyelitis Virus-Induced Disease.  In:  Molecular Biology of Picornaviruses.  (Ed. Semler, B.L. and Wimmer, E.) ASM Press, Washington, DC, 2002, pp. 427-435.

Ghadge, G.D., Slusher, B.S., Bodner, A., Dal Canto, M.,Wozniak, K., Thomas, A., Rojas, C., Tsukamoto, T., Majer, P., Miller, R.J., Monti, A.L., and Roos, R.P. Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial ALS (FALS) models. PNAS. 100:9554-9559, 2003.

ORIGINAL ARTICLES (most recent)

Ghadge, G.D., Ma, L., Sato, S., Kim, J., and Roos, R.P.  A protein critical for a mouse picornavirus-induced immune-mediated demyelinating disease has a cell type-specific antiapoptotic effect and key role in virus persistence. J. Virol . 72:8605-8612, 1998.

Lin, X., Roos, R. P., Pease, L.R., Wettstein, P., and Rodriguez, M.  A Theiler’s virus alternatively-initiated protein inhibits the generation of H-2-K-restricted virus-specific cytotoxicity.  J. Immunol.162:17-24, 1999.

Chen, H.-H., Kong, W.-P., Zhang, L., Ward, P.L., and, Roos, R.P.  A picornaviral protein synthesized out of frame with the polyprotein plays a key role in a virus-induced immune-mediated demyelinating disease.  Nature Med.1:927-931, 1995.

Sato, S., Reiner, S.L., Jensen, M.A., and Roos, R.P. Central nervous system cytokine mRNA expression  following Theiler’s murine encephalomyelitis virus infection. J. Neuroimmunol. 76:213-223, 1997.