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Advisory Committee Chair

Talene Yacoubian

Advisory Committee Members

Peter King

Anne Theibert

Scott Wilson

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Parkinson's Disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra. Gene multiplication of alpha-synuclein causes an autosomal dominant inheritance pattern of PD. A mouse model overexpressing alpha-synuclein demonstrates some of the phenotype seen in PD. In a microarray of these mice, a downregulation of angiogenin was observed prior to symptom onset, demonstrating a potential link of angiogenin to pathology in this model. Angiogenin has also been associated with the onset of Amyotrophic Lateral Sclerosis (ALS), and is neuroprotective in models of ALS through activation of the Akt pathway, a pro-survival signaling pathway. Based on these findings we hypothesized that angiogenin is protective in models of PD through activation of the Akt pathway. The goals of these studies was to determine whether 1) angiogenin was protective in cellular models of PD, 2) angiogenin required the Akt pathway to be protective, and 3) angiogenin was protective in a mouse model of PD. We first demonstrate that angiogenin is protective in two dopaminergic cell lines against toxins used to model PD. This finding supports angiogenin's function in neurons to be important for cell survival. We then demonstrate that angiogenin induces Akt phosphorylation in a dopaminergic cell line, but inhibition of Akt signaling did not inhibit angiogenin's protective response. We next investigated a mutant of angiogenin, K40I, for its ability to be protective in cellular models of PD. This mutant has previously been shown not to be protective in motoneurons and fails to activate Akt phosphorylation. Our findings revealed that K40I does not phosphorylate Akt in a dopaminergic cell line. We further demonstrate K40I still has the capacity to be protective, indicating angiogenin to promote survival of dopaminergic neurons in a different manner than motoneurons. Lastly, we investigated angiogenin's ability to be protective in a mouse model of PD. Our results demonstrate that in our experimental paradigm angiogenin was not protective, and that other delivery options to investigate angiogenin's protective effect may be necessary. These studies demonstrate that angiogenin provides a neuroprotective effect in cellular models of PD and with further investigation may be a potential therapeutic agent for PD.

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