Neurodegenerative diseases, such as Alzheimer Disease (AD) and HIV–associated neurocognitive disorder (HAND) represent a tremendous burden to healthcare and a devastating impact on society. A common feature of neurodegenerative diseases is progressive dysfunction and death of neurons in key regions of the brain. Observations of dysregulated cell cycle proteins in the brains of patients, along with research in animal models and cultured cells, suggest that aberrant functions of cell cycle proteins contribute to neuronal death and progression of neurodegenerative diseases. The p53 tumor suppressor is a key component in cell cycle signaling and cell death. p53 maintains multiple functions related to cellular homeostasis and cell fate determination, and is negatively regulated by two E3 ubiquitin ligases, MDM2 and MDMX (murine double minute X). MDM2 and MDMX promote cell survival and are implicated in several types of cancer, but the functions of MDMX in neurons are largely unknown. MDMX promotes survival in cultured neurons, but becomes degraded in response to neurotoxic stress, leading to a conclusion that MDMX acts as a “node” for stress factors in neuronal death. This thesis examines mechanisms by which MDMX promotes neuronal survival, and how MDMX functions become disrupted during neurodegenerative disease. Utilizing human tissue samples, rodent models, and pharmacological experiments in cultured neurons, we determined how MDMX is affected in AD and HAND, and how these changes relate to neuronal damage. First, we demonstrate that calpain–mediated loss of MDMX contributes to neuronal damage in a model of HAND, and that MDMX overexpression protects neurons in this model. In our second body of work, we demonstrate that neuronal MDMX is reduced in AD and in AD models due to amyloid–induced caspase activation, and that loss of MDMX function contributes to pathological processes observed in AD, including mitochondrial damage, calpain activation, and Cdk5 hyperactivity. Finally, we examine p53 as a downstream effector of MDMX in neurons. We conclude that the oncoprotein MDMX promotes neuronal survival through regulation of mitochondria, calpains, and Cdk5. Our work has identified mechanisms of MDMX degradation in two neurodegenerative diseases, whereby MDMX activity is reduced, causing dysregulation of downstream factors and neuronal damage.