Roles of Cdk5 in neurodevelopment and neurodegeneration

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Over the past year, we have made a major effort to characterize mitochondrial localization and function in the context of neurodegeneration. We find that mitochondria are excluded from the Axon Initial Segment under wild type conditions but this exclusion is lost in neurons lacking Cdk5 activity that are fated to degenerate. We have shown previously that this is the region of the axon where degeneration initiates. The significance of loss of mitochondrial exclusion is unclear as it is not observed from other experimental treatments that also induce degeneration. We continue to investigate this phenomenon. We are also in the midst of combining genetic loss of Cdk5 activity with pharmacological treatments that either enhance or suppress the effects of that genetic manipulation upon specific aspects of mitochondrial function or redox balance. The goal is to determine whether the mitochondrial and redox effects of altered Cdk5 activity are responsible for neuron loss or serve to limit that loss. All of these manipulations are validated by simultaneously tracking genetic reporters that quantify various aspects of neuronal function, number, and redox state. Data collection is currently in progress and we expect the matrix of measurements to be completed by early fall. A second series of studies is extending our characterization of the transcriptomic changes that accompany aging and mortality in the context of neurodegeneration. Alongside of that, we are collaborating with labs at NIH and UT Houston to determine whether mice display a linkage between transcriptomics of aging and presence of a bacterial microbiome similar to that we have described previously in Drosophila.