Date of Award
Doctor of Philosophy (PhD)
Neurons are constantly responding to internal and external cues as they adapt through signaling cascades and transcriptional programs. I have identified a role for the dual leucine zipper kinase (DLK) and the transcriptional program it controls in neuronal inhibition of the protein phosphatase PP2A. PP2A is an essential phosphatase, expressed in all cell types and required for survival. There is a reduction in PP2A activity in Alzheimer’s disease patient brains which is linked to increased phosphorylation of the microtubule associated protein Tau and ultimately cell death. Here, I have demonstrated that PP2A acts to restrain the DLK stress response and that DLK signaling is required for both developmental and degenerative phenotypes from PP2A inhibition. At the Drosophila neuromuscular junction loss of PP2A activity causes synaptic overgrowth which requires DLK signaling and induction of a downstream transcriptional response. Further, DLK is also required for neuronal cell death following PP2A inhibition in mammalian cortical neurons in vitro. Importantly, DLK signaling does not affect the phosphorylation of Tau and, indeed, this neuronal cell death is demonstrated to be a Tau-independent process. Hence, loss of PP2A function triggers two independent neuropathologies: 1) Tau hyperphosphorylation and 2) DLK activation and subsequent neuronal cell death.
Chair and Committee
Paul Taghert, John Cirrito, Celeste Karch, Andrew Yoo,
Hayne, Margaret, "Linking Neuronal Protein Phosphatase 2A to the DLK Stress Kinase Signaling Cascade" (2021). Arts & Sciences Electronic Theses and Dissertations. 2497.