Roles of Cdk5 in neurodevelopment and neurodegeneration

National Institute Of Neurological Disorders And Stroke

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Abstract

A primary goal of our work in neurodegeneration has been to dissect the relationships among the various mechanisms of pathology. In the past year, we have made significant advances in this effort (published in three papers). In the previous year, we had developed a method for measuring the physiological age of an individual or population by quantitative expression profiling and used this method to show that one mechanism of degeneration in our fly model is acceleration of the onset of aging. (The method we developed has since been used by a large number of labs in the aging field, and its principles have been applied to proteomic and metabolomic datasets, as well.) Given that this provided us with a way to account quantitatively for the contribution of aging to degeneration, it also gave us the ability to subtract that effect from expression profiles of our degeneration mutant and thus isolate non-aging components of degeneration. This revealed the existence of a second pathway, orthogonal to aging, by which inhibition of autophagy causes neurotoxic activation of the innate immune response, and that it is the resulting hyperexpression of immune effector proteins, such as antimicrobial peptides, that actually cause the death of a sensitive neuronal population (dopamine neurons; reported in Shukla, 2019 a and b). In parallel to our identification of an autophagy/immunity pathway of degeneration, we also identified yet a third pathway. In characterizing the phenotype of our neurodegeneration mutant (a null mutant of the gene encoding the Cdk5 activating subunit, p35), we previously demonstrated that the mutation causes severe disruption of the axonal cytoskeleton, and in particular of the axon initial segment (AIS), that is correlated with cell degeneration. Since we published this, other labs have shown that the same correlation is observed in other models of degeneration, such as a tauopathy model in the mouse. However, neither their work nor our previous work could provide evidence as to whether AIS defects are causal for degeneration, or simply correlated. In our new work we disrupted AIS structure directly, by expression of a dominant-negative form of the Ankyrin paralog that nucleates the AIS, and found that this was sufficient to cause axon fragmentation and neuron loss. We further showed that the mechanism of ankyrin-induced AIS loss is genetically separate from the mechanism of Cdk5/p35-dependent AIS disruption. Together, these data therefore provide strong evidence that disruption of the axonal cytoskeleton, and of neuronal excitability through dysregulation of the AIS, are indeed a third, distinguishable, causal pathway of neurodegeneration in our tauopathy model in the fly (Spurrier, et al. 2019). We now plan to extend our analysis of the three-way relationship of aging, immunity and degeneration; investigate how mitochondrial dysfunction and synapse loss fit into the picture of degeneration that we have developed, and begin efforts to screen for mutants that can modulate the onset of degeneration in flies that are genetically predisposed to this pathology.