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VISUAL ARRESTIN INTERACTIONS WITH CLATHRIN ADAPTOR AP-2
REGULATE PHOTORECEPTOR SURVIVAL
by
Hormoz Moaven
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(NEUROSCIENCE)
August 2012
Copyright 2012 Hormoz Moaven
Object Description
| Title | Visual arrestin interactions with clathrin adaptor AP-2 regulate photoreceptor survival |
| Author | Moaven, Hormoz |
| Author email | moaven@usc.edu;hmoaven@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts And Sciences |
| Date defended/completed | 2012-03-13 |
| Date submitted | 2012-07-25 |
| Date approved | 2012-07-25 |
| Restricted until | 2012-07-25 |
| Date published | 2012-07-25 |
| Advisor (committee chair) | Chen, Jeannie |
| Advisor (committee member) |
Sampath, Alapakkam Hinton, David |
| Abstract | Autosomal dominant retinitis pigmentosa (ADRP) is a blinding disorder whose most frequent causes are rhodopsin mutations. Of the more than 100 rhodopsin mutations that have been found, some disrupt the intramolecular interactions that constrain the molecule in an active conformation. This leads to a detrimental effect on the phototransduction cascade, which ultimately leads to retinal degeneration. One such mutation is Lys296Glu (K296E), in which case a lysine residue is replaced with a glutamic acid residue. It has been previously shown that opsin mutations in Drosophila form stable opsin/arrestin complexes that causes retinal degeneration via photoreceptor cell death. Similarly, mice expressing the K296E rhodopsin mutation also show progressive degeneration due to formation of a stable K296E/arrestin1 complex that is toxic to mammalian photoreceptors. The degeneration in Drosophila has been attributed to endocytosis of the rhodopsin/arrestin complexes via AP-2/clathrin binding. By effectively altering the genetics of K296E mice, I investigated whether the underlying causes and mechanisms that give rise to retinal degeneration associated with the K296E mutation are comparable to those found in Drosophila. This was achieved by substituting arrestin1 with a naturally occurring arrestin1 splice variant, p44, in which case the C-terminus is truncated at residue 370. This truncation eliminates the AP-2 binding domain and in turn prevents endocytosis. Expression of p44 in arrestin1 knockout mice reveals normal binding to rhodopsin and phototransduction activity. Accordingly, expressing p44 in K296E⁺/Arr⁻/⁻ mice should indicate whether endocytosis is mediating retinal degeneration and support our hypothesis that cell death is resultant of AP-2-mediated endocytosis of the K296E/Arrestin1 complex. ❧ Furthermore, I provide insight into another form of retinal degeneration, Oguchi disease, which is hallmarked by an inability to effectively dark-adapt from bright light conditions. The underlying cause of the disease has been identified as a mutation in arrestin and/or rhodopsin kinase, where a defect in either protein would prolong recovery from a light response. A further investigation of the roles of arrestin and rhodopsin kinase is still needed. I show that arrestin knockout mice exhibit a reduced rate of rhodopsin regeneration, thus reducing rod sensitivity. I go on to investigate whether specific phosphorylation residues on the C-terminus of rhodopsin regulate proper recovery kinetics and present their possible roles in dark adaptation. ❧ Lastly, a mutation affecting the rod cGMP-phosphodiesterase causes a form of retinitis pigmentosa. The rd1 mouse model of this disease exhibits an accumulation of cGMP concentrations inside the rod photoreceptor, which causes cell death due to the increase in cytosolic Ca2+ influx through cGMP-gated ion channels. I investigated the possible therapeutic treatment of CNG channel blockers in the rd1 mouse model. Preliminary treatments show promising results as retinal degeneration was slowed in several cases. |
| Keyword | retina; retinitis pigmentosa; rod; photoreceptor; rhodopsin; retinal degeneration; phototransduction; arrestin; rhodopsin kinase; phosphorylation; CNG channels; k296e; p44 |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Moaven, Hormoz |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-MoavenHorm-993.pdf |
Description
| Title | Page 1 |
| Full text | VISUAL ARRESTIN INTERACTIONS WITH CLATHRIN ADAPTOR AP-2 REGULATE PHOTORECEPTOR SURVIVAL by Hormoz Moaven A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (NEUROSCIENCE) August 2012 Copyright 2012 Hormoz Moaven |
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