Roles of Cdk5 in neurodevelopment and neurodegeneration

National Institute Of Neurological Disorders And Stroke

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Abstract

It is well established that adult-onset neurodegeneration is associated with changes in mitochondrial function in general, and altered cellular oxidative state in particular. It has, however, been difficult to use these insights to improve treatment for neurodegenerative disease. Therefore, we stepped back to test critically the roles of mitochondrial and redox changes in disease progression. In particular, we investigated the role played by changes of neuronal oxidative state in the degeneration process in vivo. We found that some oxidative changes that are commonly interpreted as pathogenic “oxidative stress”, based on cell culture and in vitro studies, actually have little or no effect on organismal health in vivo, and others actually promote organismal health (extend lifespan), they do not impair health. In yet other circumstances, we found that an "antioxidant" agent that is widely used to reduce oxidative stress is actually deleterious to survival, not because of the direct effect of the drug itself but because the drug induces a homeostatic response in the animal, and it is that homeostatic response that is deleterious. These observations help explain why efforts to treat aging and degeneration with antioxidant therapies have generally been unsuccessful in the past. They also underscore the need to perform in vivo tests to validate the effects of genetic and pharmacological manipulations directly in target neuronal populations, both acutely and chronically, before moving to clinical applications. Our studies of the link between oxidative stress and organismal survival inevitably raised the question of how aging kills the individual in the non-diseased state. Essentially all studies of aging begin from the assumption that death is merely a collapse of biological organization that occurs as the natural consequence of the dysfunctions of aging. Various observations we made in our analysis of aging, however, forced us to consider the alternate possibility that death is a discrete process of its own, and to ask whether it could be distinct from aging per se. To ask this question we generated RNA expression profiling data from single individuals and developed a set of novel analytical methods to query that data. We found that dying is a discrete process, following after aging, and presumably triggered by it, but molecularly distinct from aging itself. We also found that the outlines of the dying process have been conserved through more than 500Myr of evolution, all the way to C. elegans. It remains to be seen whether they are also conserved in the vertebrate lineage.