Investigating the role of Hip1 in Huntington Disease and Parkinson Disease models in Drosophila melanogater

Slade, Frankie Amanda (2018) Investigating the role of Hip1 in Huntington Disease and Parkinson Disease models in Drosophila melanogater. Masters thesis, Memorial University of Newfoundland.

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Abstract

Huntington Disease (HD) is a progressive neurodegenerative disorder characterized by the loss of cognition and motor ability. Beginning in the dysfunction of the GABAergic neurons, HD has been mainly attributed to an increased number of CAG repeats in the Huntingtin gene, resulting in an extended polyglutamine tract within the protein. This expansion prevents the normal interaction between the proteins encoded by Htt and Huntingtin interacting protein 1 (Hip1). Conserved sequences between human and Drosophila Hip1 allow examination of the protein in D. melanogaster to be used as a model for human HD. Analysis of the loss of function of Hip1 in a pan-neuronal fashion resulted in an increase in average lifespan and decrease in motor ability. Overexpression of Hip1 resulted in a decrease in both lifespan and motor ability, suggesting a delicate balance of Hip1 in healthy cells. Investigation of the biological effects of altered Hip1 expression may provide insights into a possible role for Hip1 in HD pathogenesis. The progression of Parkinson Disease (PD) is similar to that of HD – generally occurring later in life, and affecting cognitive ability and motor function. Associated with the death of dopamingeric neurons, impairment of a number of genes has been implicated in disease progression. Recently, a polymorphism in Huntingtin interacting protein 1 Related (Hip1R), was identified as a risk-factor for PD. The Hip1R gene is not found in D. melanogaster, but is considered an orthologue of Hip1, which is conserved across species. Directed manipulation of the single Drosophila Hip1 in the dopaminergic neurons was carried out to provide an in vivo model of disease progression and symptom development. Investigation of motor ability and longevity of D. melanogaster upon overexpression and loss of function of Hip1 was completed. Loss of expression of Hip1 in the dopaminergic neurons, through the use of RNAi, decreased the locomotor ability of the flies and increased the average lifespan. Overexpression of Hip1 in the dopaminergic neurons revealed the opposite effect, improving locomotor ability and slightly decreasing average lifespan. This suggests that a delicate balance of Hip1 exists in the dopaminergic neurons, and alteration of expression affects the motor ability and life expectancy. Maintaining a healthy balance of Hip1 in the dopaminergic neurons may offer a new therapeutic option for loss of locomotor ability and pre-mature death. Further investigation of Hip1R and its role in human disease progression is needed, and may be crucial to our understanding of PD in order to provide new therapeutic targets.

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