While the role of mitochondrial dysfunction has been proposed in neurodegenerative diseases, the exact mechanism of mitochondrial pathogenesis is unclear. Our preliminary studies show that hormone receptors, estrogen receptors (ERs), and cAMP response elements binding protein (CREB) are present in the mitochondrial matrix of neurons. CREB directly binds to cAMP response elements (CREs) in the promoter regions (D-loop) of mitochondrial DNA. We also show that CREB is transcriptionally active in mitochondria and hypothesize that the regulation of mitochondrial gene expression by mitochondrial CREB may underlie some of the established protective effects in neuronal survival. This data implies that mitochondrial localization of ERs and CREB could be regulated by novel signaling pathways in the intact central nervous system and that their functions in the mitochondria might be important in neuronal survival. Therefore, we propose that the levels and activities of mitochondrial hormone receptors and transcription factors, which induce mitochondrial gene transactivation, may contribute to mitochondrial dysfunction and the subsequent neuronal loss observed in Huntington's disease (HD). Thus, the specific aims of our proposed study are: 1) To identify the topographic brain distribution of mitochondrial ERs and characterize mitochondrial estrogen receptor element (ERE) sites and interaction with CREB in neurons. 2) To determine the regulatory mechanism of mitochondrial ERs and CREB-mediated mitochondrial transcription. Protein Kinase A (PKA) is a well known enzyme for activation of ERs and phosphorylating CREB at Ser133. In this context, we propose that PKA localizes into the mitochondrial matrix and that mitochondrial PKA activity may play a role in the phosphorylation and transactivation of mitochondrial ERs and CREB. We will further characterize mitochondrial ER, PKA, and CREB activity in mouse models of HD. 3) To develop therapeutic approaches to target mitochondrial ERs and CREB in vitro and in vivo in transgenic and Knock-in HD mice expressing short segment and full length mutant huntingtin. We will determine whether specific estrogen receptor modulators (SERMs) augment mitochondrial PKA activity and mitochondrial ER and CREB phosphorylation to induce mitochondrial gene transcription that influences neuronal survival. These studies will provide novel mechanisms for preventing mitochondrial transcriptional dysfunction and help in the design of applicable compounds that modulate mitochondrial function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052724-03
Application #
7216230
Study Section
Special Emphasis Panel (ZRG1-NDBG (02))
Program Officer
Sutherland, Margaret L
Project Start
2005-07-15
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$248,648
Indirect Cost
Name
Boston University
Department
Neurology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Lee, Junghee; Hyeon, Seung Jae; Im, Hyeonjoo et al. (2016) Astrocytes and Microglia as Non-cell Autonomous Players in the Pathogenesis of ALS. Exp Neurobiol 25:233-240
Lee, Junghee; Kosaras, Bela; Del Signore, Steve J et al. (2011) Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington's disease mice. Acta Neuropathol 121:487-98
Lee, J; Hwang, Y J; Boo, J H et al. (2011) Dysregulation of upstream binding factor-1 acetylation at K352 is linked to impaired ribosomal DNA transcription in Huntington's disease. Cell Death Differ 18:1726-35
Lee, Junghee; Boo, Jung Hyun; Ryu, Hoon (2009) The failure of mitochondria leads to neurodegeneration: Do mitochondria need a jump start? Adv Drug Deliv Rev 61:1316-23
Lee, Junghee; Ryu, Hoon; Kowall, Neil W (2009) Differential regulation of neuronal and inducible nitric oxide synthase (NOS) in the spinal cord of mutant SOD1 (G93A) ALS mice. Biochem Biophys Res Commun 387:202-6
Lee, Junghee; Ryu, Hoon; Kowall, Neil W (2009) Motor neuronal protection by L-arginine prolongs survival of mutant SOD1 (G93A) ALS mice. Biochem Biophys Res Commun 384:524-9
Lee, Junghee; Kannagi, Mari; Ferrante, Robert J et al. (2009) Activation of Ets-2 by oxidative stress induces Bcl-xL expression and accounts for glial survival in amyotrophic lateral sclerosis. FASEB J 23:1739-49
Lee, Junghee; Sharma, Swati; Kim, Jinho et al. (2008) Mitochondrial nuclear receptors and transcription factors: who's minding the cell? J Neurosci Res 86:961-71
Ryu, Hoon; Ferrante, Robert J (2007) Translational therapeutic strategies in amyotrophic lateral sclerosis. Mini Rev Med Chem 7:141-50
Stack, Edward C; Del Signore, Steven J; Luthi-Carter, Ruth et al. (2007) Modulation of nucleosome dynamics in Huntington's disease. Hum Mol Genet 16:1164-75

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