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Transcriptional Regulation of Alpha-synuclein by GATA2 in Substantia Nigra

Horowitz, Max (2012) Transcriptional Regulation of Alpha-synuclein by GATA2 in Substantia Nigra. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Parkinson’s disease (PD) is a chronic, progressive movement disorder that affects millions of patients and their families worldwide. Treatment options address some of the symptoms but do not affect the progression of the disease. Central to the motor symptoms of PD are due, in part, to the slow, progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the consequent depletion of dopaminergic neurotransmission in the striatum. As these cells die, they accumulate toxic levels of various substances, such as the aggregation-prone protein alpha-synuclein (a-syn, SNCA) and iron. It is known that expression of SNCA is aberrantly high in SNc dopaminergic neurons in the PD brain, but the transcriptional mechanisms that participate in this dysregulation are poorly understood. Recently, GATA2, a transcription factor known for its critical role in hematopoiesis, was shown to regulate SNCA positively and directly in vitro; however, it is unknown whether this mode of regulation occurs in vivo and is thereby relevant to PD. In this dissertation project, we assessed the relevance of GATA2 in PD by testing two hypotheses in a mammalian model: 1) GATA2 positively regulates SNCA in vivo in SNc neurons, and 2) silencing GATA2 expression in SNc neurons confers protection against the parkinsonian neurotoxin, rotenone. To test these hypotheses, it was necessary first to validate rat as a suitable model for investigating GATA2 function in adult brain and to develop reagents for silencing GATA2 expression in vivo. Using a viral-mediated gene silencing approach, we found that GATA2 positively regulates SNCA in SNc dopaminergic neurons in adult rat. However, silencing GATA2 was not protective against rotenone treatment in the rat model of PD. Our findings are significant in that they provide the first in vivo demonstration of a transcription factor that regulates SNCA, a gene of central importance to PD pathogenesis. Although our data suggest that GATA2 is not a useful therapeutic target for PD, our findings shed some light on the role of GATA2 in adult SNc dopaminergic neurons, thus contributing to our understanding of GATA transcription factor biology in the adult brain.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Horowitz, Maxmaxx.horowitz@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairHastings, Teresahastingst@upmc.eduTHASTING
Committee MemberAizenman, Eliasredox@pitt.eduREDOX
Committee MemberBurton, Edwardeab25@pitt.eduEAB25
Committee MemberStandaert, Daviddstandaert@uab.edu
Committee MemberSved, Alansved@pitt.eduSVED
Thesis AdvisorGreenamyre, J. Timothyjgreena@pitt.eduJGREENA
Date: 26 July 2012
Date Type: Publication
Defense Date: 17 May 2012
Approval Date: 26 July 2012
Submission Date: 25 July 2012
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 184
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Parkinson's disease, GATA transcription factor, rotenone, alpha-synuclein, in situ hybridization, GATA2
Date Deposited: 26 Jul 2012 18:33
Last Modified: 26 Jul 2017 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/13171

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