Dissertation Defense: Andrew Wodrich
Candidate: Andrew Wodrich
Major: Neuroscience
Advisors: Edward Giniger, Ph.D. and Brent T. Harris, M.D., Ph.D.
Investigations of Mitochondrial Function and Distribution in Cdk5-Associated Neurodegeneration in Drosophila
Age-related neurodegenerative diseases (NDDs) represent a significant personal and public health burden, in large part, because no therapeutics exist to slow the course of these diseases. Many of the pathophysiological features that are shared amongst these diseases are associated with mitochondria. However, it remains unclear how changes in mitochondria observed in age-related NDDs contribute to, or potentially counteract, the cellular and organismal decline accompanying these diseases. Here, I utilize a Drosophila melanogaster model that relies upon reducing the activity of cyclin dependent kinase 5 (Cdk5) to investigate the roles of mitochondrial function and distribution changes in age-related NDD.
I first examine Cdk5-associated changes in mitochondrial function, and I find the mitochondrial redox environment to be perturbed. To understand whether these changes are contributing to or counteracting Cdk5-associated neurodegeneration, I utilize a pharmacologic approach to modulate the mitochondrial redox state. In Cdk5-affected tissue, I unexpectedly find lower mitochondrial H2O2 concentration and, contrary to what might be expected, this change is contributing to the demise of the organism. Perhaps most important, I find that manipulating the mitochondrial glutathione redox potential, an integrative marker of multiple ROS and antioxidant pathways, affects Cdk5-associated survival through the induction of compensatory metabolic responses and not from changes in the final, absolute level of this redox parameter. The presence of such compensatory mechanisms and their implications for disease have been previously underexplored, and I show here that these compensatory responses can be modulated by both age and a neurodegeneration-associated perturbation, reduction of Cdk5 activity. Finally, I show that the distribution of mitochondria is unlikely to be playing a causal role in Cdk5-associated neurodegeneration, isolating the mitochondrial deficits in this model to the function of the mitochondria rather than their subcellular localization. Interestingly, I did observe changes in mitochondrial localization at the axon initial segment which may be relevant to the normal physiology of neurons. In summary, the work presented in this dissertation uncovers unexpected insights into how changes observed to correlate with age-related neurodegeneration in a Drosophila model are implicated in that pathology.