Molecular mechanisms of programmed cell death (apoptosis) and its role in neuronal disease and viral pathogenesis.

Programmed cell death is an essential process for eliminating cells during development, tissue remodeling and virus infections. Dysregulation of programmed cell death leads to a variety of disease states. For example, insufficient cell death underlies the development and progression of cancer, while excessive cell death is responsible for a variety of neurological and other disease states. We have shown that viruses can trigger cells to activate a cellular apoptotic death pathway (Nature, 361:739-742, 1993). Induction of apoptotic cell death induced by virus infections can be either a host defense mechanism or result in a disease state (J. Virol. 70:1828-1835, 1996). Modulation of the cell death pathway by viral and cellular gene products can alter pathogenesis of disease and contribute to the oncogenic potential of viruses (Proc. Natl. Acad. Sci. USA 94: 690-694, 1997). To study genes that regulate the cell death pathway, we generated a Sindbis virus vector capable of expressing a variety of cellular factors that regulate apoptotic cell death (Nature 379:554-556, 1996). This vector is a powerful tool that can be used to study and characterize cell death regulators both in cell culture and in a mouse model (Proc. Natl. Acad. Sci. USA 93:4810-4815, 1996). Using this strategy, we have identified a number of viral and cellular factors that regulate apoptosis induced by viruses and other stimuli (EMBO J. 15:2685-2694, 1996; J. Virol. 71:4118-4122, 1997; J. Virol. 72:327-338, 1998). Because Sindbis virus specifically targets neurons of the central nervous system, we have a unique reagent with which to study neuronal disease resulting from genetic mutations, virus infections and other insults. Using this strategy we have uncovered surprising new functions for members of the BCL-2 family of cell death regulators (Nature Med. 5:832-835, 1999). This tool also allowed us to demonstrate that the genetic mutations in patients with spinal muscular atrophy convert an anti-apoptotic SMN protein into a killer protein (Proc. Natl. Acad. Sci USA 97:13312-13317, 2000). The mechanisms by which SMN and other cell death factors modulate neuron-specific survival are currently under study. We have also shown that other inhibitors of cell death, including BCL-2 family members, are cleaved by caspases during cell death to produce fragments with potent cell killing function (Science 278:1966-1968, 1997; Proc. Natl. Acad. Sci. 95:554-559, 1998). In addition, we have discovered new factors such as Aven that regulate programmed cell death, and we have delineated important differences between viral and cellular homologues of apoptosis regulators (Molec. Cell 6:31-40, 2000; J. Virol. 74:5024-5031, 2000). These and other findings in our laboratory have yielded a new hypothesis about how cell death regulators work. That is, cell death inhibitors function as sensors of cell damage and are converted into death inducers to facilitate the cell’s demise.

Molecular Microbiology and Immunology, Molecular mechanisms of programmed cell death (apoptosis) and its role in neuronal disease and viral pathogenesis.