Transcriptional Regulation of Alpha-synuclein by GATA2 in Substantia Nigra

[摘要] 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.

[发布机构] the University of Pittsburgh