Throughout this application, various publications are referenced by author and date. Full citations for these publications may be found listed alphabetically at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Neuronal death by apoptosis is a normal feature of development in which it appears that the death program is triggered by the failure of a given neuron to compete for limiting supplies of target-derived neurotrophic factors. Neurons also undergo apoptotic death in the post-developmental period when deprived of appropriate trophic factors or when subjected to any of a variety of stresses and injuries. Apoptosis also accounts for at least a portion of cellular loss in degenerative neurological diseases including Alzheimer's disease and amyotrophic lateral sclerosis (Coyle and Puttfarcken, 1993; Schapira, 1995; Williams, 1995; Brown, 1995).
Neuronal apoptotic death may be precipitated by widely different initiating causes. In the rat pheochromocytoma PC12 line, a commonly used model for neuronal differentiation and cell death, apoptosis may be triggered by either trophic factor/NGF withdrawal as well as by sympathetic neurons (Greene, 1978; Rukenstein et al., 1991; Mesner et al., 1992; Pittman et al., 1993; Lindenboim et al., 1995 Batistatou and Greene, 1991) or oxidative stress induced by down-regulation of Cu++/Zn++ superoxide dismutase (SOD1) (Troy and Shelanski, 1994; Troy et al., 1996a,b,c). The initiating mechanisms of death appear to be distinct in each instance. Apoptosis triggered by nerve growth factor (NGF) deprivation is blocked by cAMP analogs (Rydel and Greene, 1988; Rukenstein et al., 1991) and high concentrations of N-acetyl cysteine (Ferrari et al., 1995) whereas these agents do not inhibit death induced by down regulation of superoxide dismutase (SOD1) (Troy et al., 1996 a,c). In contrast, the latter is blocked by vitamin E (Troy and Shelanski, 1994) and inhibitors of nitric oxide (NO) synthase (Troy et al. 1996a), which have no effect on apoptosis evoked by NGF withdrawal (Ferrari et al., 1995; Farinelli et al., 1996). Despite these initial mechanistic differences, there is evidence for common or similar downstream elements in the pathways that lead to death in both paradigms.