The Regulation of Neuronal Survival through the Modulation of Aberrant Cell Cycle Re-Entry

The complex nature of the neuron is made that much greater knowing there are billions of them forming trillions of synaptic connections all while working in concert with billions of non-neuronal glial cells. To further complicate the highly intricate environment that forms the brain, upon maturation neurons become senescent, or post-mitotic, and will no longer regenerate. Nucleophosmin 1 (NPM1) is a highly abundant and ubiquitously expressed nucleolar phosphoprotein. While actively investigated for its role in the regulation of many cellular processes critical for proliferative cells, little is known about its role in the brain. The primary focus of this dissertation is to examine the effect of NPM1 on the regulation of neuronal viability. The dissertation is divided into the following four chapters: I begin in chapter 1 by providing an overview of the mechanisms regulating a form of programmed cell death known as apoptosis or cell suicide. While there are many causes that can lead to the initiation of neuronal apoptosis, one well-accepted method is through a neuron’s aberrant attempt to divide. In order to understand how this may occur, this chapter provides an overview of the complex regulation of the cell cycle.
In chapter 2, I summarize what is currently known about the roles of NPM1 in actively dividing cells. Little has been published on neuronal NPM1. As such, this chapter concludes by describing these few studies, as well as what insights we can gain about its role in these cells from its functions in proliferative ones. Chapter 3 describes a complex nature for neuronal NPM1. I show that while neurons require this protein for their normal healthy survival, increasing its expression is toxic. This toxicity is regulated by NPM1’s ability to translocate to the cytoplasm and oligomerize. If restricted to the nucleus, which results in an inability to oligomerize, NPM1 no longer induces death and becomes fully protective against apoptosis.
Finally, in chapter 4 I extend previously published findings with new and unfinished data describing the neuroprotective roles for SIRT1 and SIRT5, two members of the Class III histone deacetylases (HDACs) that are collectively know as the sirtuins. I describe how SIRT1 is able to confer a protective effect in a deacetylase independent manner through a dependence on HDAC1. Lastly, I provide evidence that SIRT5 is able to protect neurons in a PKA-dependent manner.