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Characterization of an inducible model of a genetic prion disease in Drosophila melanogaster / by Archana Murali.

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Author	Murali, Archana.
Title	Characterization of an inducible model of a genetic prion disease in Drosophila melanogaster / by Archana Murali.
Date	2014
Abstract	Prion diseases are progressive disorders that affect the central nervous system leading to memory loss, personality changes, ataxia and neurodegeneration. In humans, these disorders include Creutzfeldt-Jakob disease, kuru and Gerstmann-Str?ussler-Scheinker (GSS) syndrome, the latter being a dominantly inherited prion disease associated with missense mutations in the gene that codes for the prion protein. The exact mechanism by which mutant prion proteins affect the central nervous system and cause neurological disease is not well understood. We have generated an inducible model of GSS disease in Drosophila melanogaster by temporally expressing wild type and a misfolded form of the murine prion protein in cholinergic neurons. In our first study, we have characterized this model and shown that flies accumulating prion proteins develop motor abnormalities which are associated with electrophysiological defects in cholinergic neurons. When expression of the prion protein is blocked, both behavioral and electrophysiological defects can be reversed. This represents the first case of reversibility reported in a model of genetic prion disease. Additionally, we observed that endogenous mechanisms exist within Drosophila that are capable of clearing accumulated protein. We have further shown the involvement of the unfolded protein response and the proteasome in the clearance of prion protein. In the second study, we have characterized a novel modifier of the prion disease phenotype in flies. Angiotensin converting enzyme (Ance) was identified from a large scale screen conducted in our lab. When expressed with the prion protein in cholinergic neurons. Ance can significantly improve the behavior of our prion fly model without affecting a change in total prion protein levels or localization. Furthermore, the rescue activity of Ance is not restricted to one neurodegenerative disease. We have demonstrated that Ance can suppress the phenotype associated with A-beta expression in an Alzheimer's disease model. Lastly we have shown that Ance does not rescue a Drosophila model of spinocerebellar ataxia. We speculate that the action of Ance within cholinergic neurons stabilizes the activity of these neurons and therefore affects a rescue in prion and Alzheimer disease models where mutant proteins are expressed and misregulate cholinergic neuronal activity
Description	xiii, 83 leaves : ill. (some col.)
Format	application/pdf
College	Dartmouth College. Department of Biological Sciences.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1227

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Characterization of an inducible model of a genetic prion disease in Drosophila melanogaster / by Archana Murali.

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