Roles of Cdk5 in neurodevelopment and neurodegeneration

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We previously developed a potential Drosophila model of mammalian neurodegenerative disease by inactivating the protein kinase Cdk5/p35. This is the fly homolog of one of the two main proteins responsible for phosphorylating tau into the form found in the neurofibrillary tangles that are characteristic of many forms of human neurodegeneration. Inactivation of this protein kinase in vivo in the fly has a variety of phenotypic consequences that are reminiscent of phenomena seen in human neurodegenerative disease. In experiments that have been favorably reviewed for publication and are currently undergoing final revision prior to resubmission, we have now found that Cdk5 also regulates a developmentally-programmed form of axonal and dendritic disassembly in the fly. Programmed pruning and remodeling of the mushroom bodies in the Drosophila central brain bears many mechanistic similarities to the neurite loss seen in disease. We find that Cdk5 controls the timing and rate of axonal and dendritic disassembly, and that it does so in part by controlling the stability of the microtubule cytoskeleton. We also find, however, that Cdk5 must use at least one other mechanism, acting in parallel to its effects on microtubules, which more directly targets the final fragmentation of axons and dendrites late in the neurite disassembly cascade. These data begin to give us a way to discriminate the different Cdk5-dependent mechanisms that contribute to overall neurite disassembly in development and disease. In parallel with these targeted developmental and phenotypic studies of Cdk5/p35, we have also been performing a more broadly focused systems analysis of the kinase. We find that the genome-wide gene expression profile of flies lacking kinase activity shows extremely strong correlation to that of flies with hyper-activated kinase. This agrees with the physiological analysis of under/over expression in mammals, where gain and loss of function of Cdk5/p35 both result in neuronal death in cell culture and neurodegeneration in vivo. Remarkably, however, the gene expression profile of flies with altered Cdk5/p35 activity also shows close correlation with the profile of changes observed during aging. This begins to hint, perhaps, at a possible mechanistic basis for the long-recognized association between neurodegenerative disease and aging.