Parkinson's disease (PD) is associated with pathological increases in iron and 1-synuclein (1-syn) in the substantia nigra (SN), and these features are reproduced animal models of PD that use the pesticide rotenone. Both 1-syn and iron accumulate in nigral dopamine neurons and are cytotoxic;however, the mechanism underlying their pathological accumulation is unknown. We have identified a transferrin/transferrin receptor 2 (TfR2)-mediated mechanism for iron accumulation in nigral dopamine neurons, and have found that TfR2 levels are increased in dopamine neurons in the rotenone rat. GATA transcription factors, whose role has been well characterized in hematopoiesis, have recently been shown to positively regulate the expression of 1-syn in vitro. The isoform GATA2 is expressed in human SN, and preliminary studies have localized GATA2 to dopamine neurons in rat SN. Preliminary data indicate that GATA2 positively regulates TfR2 transcription in vitro. Thus it is possible that GATA2 positively and coordinately regulates both 1-syn and TfR2 in nigral dopamine neurons in vivo, and that therapeutic GATA2 inhibition may simultaneously ameliorate the deleterious effects of both 1-syn and iron in PD. This proposal will use in vivo viral-mediated gene silencing in rat SN to test the following hypotheses: 1) GATA2 regulates 1-syn and TfR2 in rat nigral dopamine neurons, and 2) inhibition of GATA2 in nigral dopamine neurons leads to decreased accumulation of 1-syn and iron following rotenone treatment, thereby attenuating nigrostriatal degeneration. This work will examine how two apparently disparate pathological features of PD-the accumulation of 1-synuclein and the accumulation of iron within nigral dopamine neurons-may be coordinately attenuated via inhibition of the transcription factor, GATA2, using in vivo viral-mediated gene silencing. Successful completion of these aims would establish GATA2 as a potential therapeutic target that could be exploited using gene therapy to ameliorate the cellular toxicity associated with both 1-syn and iron accumulation in human PD.

Public Health Relevance

Parkinson's disease (PD) is a neurodegenerative disorder that affects over one million Americans and currently no therapies alter disease progression. This research will evaluate whether a specific gene therapy intervention prevents brain degeneration by simultaneously acting on two important pathological features of the disease. A novel therapeutic intervention for eventual clinical use in human PD may be identified through this work, thereby addressing a major public health burden.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30ES019376-03
Application #
8308686
Study Section
Special Emphasis Panel (ZRG1-F01-L (20))
Program Officer
Humble, Michael C
Project Start
2010-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$47,232
Indirect Cost
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Horowitz, Maxx P; Milanese, Chiara; Di Maio, Roberto et al. (2011) Single-cell redox imaging demonstrates a distinctive response of dopaminergic neurons to oxidative insults. Antioxid Redox Signal 15:855-71