Reduced Foxp1 Expression as a Contributing Factor in Huntington's Disease

Abstract

Neurodegenerative diseases affect the quality of life and place huge emotional, physical and economic strain on families and society. Neurodegenerative diseases feature an uncontrolled neuronal apoptosis. There are currently treatments which are aimed at alleviating the symptoms of the disease, but there are no treatments which stop the uncontrolled loss of neurons in the brain. A proper understanding of the underlying mechanisms of neurodegeneration will aid in developing better treatment strategies against the disease. Forkhead proteins play a critical role in regulating the transcriptional profile in cells, and Forkhead box protein P1 (Foxp1), a member of the forkhead family of proteins, is highly expressed in striatum and cortex of the brain. While earlier studies on Foxp1 have been focused on its role in cancer and immunological function, we discovered a neuroprotective role of Foxp1. The focus of my dissertation is on identifying the mechanism of neuroprotection of Foxp1.

Chapter 1 of this dissertation reviews the current literature on mechanisms of neurodegeneration in Huntington’s disease (HD) and how aberrant reentry of post mitotic neurons into cell cycle is a recurring theme in many neurodegenerative diseases. I also discuss the expression and regulation of forkhead proteins in the brain and also discuss the recent findings regarding evidences of cell cycle dysfunction in neurons.

In Chapter 2, I describe the research done on neuroprotective protein, Foxp1, the expression of which is decreased in human HD patients and in mouse models of HD, and overexpressing Foxp1 can protect neurons from mutant Huntingtin toxicity. Foxp1 was also found to be neuroprotective against a wide range of apoptotic stimuli, and the neuroprotection of Foxp1 occurs by the up-regulation of p21Waf1/Cip1, a well-known inhibitor of cell cycle.

In Chapter 3, I summarize my findings on neuroprotection of Foxp1 and discuss the therapeutic potential of repurposing cancer treatment drugs in the treatment of neurodegenerative diseases.