Nuclear Proteins

Publication Title: 
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

There is substantial evidence that bioenergetic defects and excitotoxicity may play a role in the pathogenesis of Huntington's disease (HD). Potential therapeutic strategies for neurodegenerative diseases in which there is reduced energy metabolism and NMDA-mediated excitotoxicity are the administration of the mitochondrial cofactor coenzyme Q10 and the NMDA antagonist remacemide.

Ferrante, Robert J.
Andreassen, Ole A.
Dedeoglu, Alpaslan
Ferrante, Kimberly L.
Jenkins, Bruce G.
Hersch, Steven M.
Beal, M. Flint
Publication Title: 
Science (New York, N.Y.)

Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity.

Dunah, Anthone W.
Jeong, Hyunkyung
Griffin, April
Kim, Yong-Man
Standaert, David G.
Hersch, Steven M.
Mouradian, M. Maral
Young, Anne B.
Tanese, Naoko
Krainc, Dimitri
Publication Title: 
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

Huntington's disease (HD) results from polyglutamine expansion in huntingtin (htt), a protein with several consensus caspase cleavage sites. Despite the identification of htt fragments in the brain, it has not been shown conclusively that htt is cleaved by caspases in vivo. Furthermore, no study has addressed when htt cleavage occurs with respect to the onset of neurodegeneration. Using antibodies that detect only caspase-cleaved htt, we demonstrate that htt is cleaved in vivo specifically at the caspase consensus site at amino acid 552.

Wellington, Cheryl L.
Ellerby, Lisa M.
Gutekunst, Claire-Anne
Rogers, Danny
Warby, Simon
Graham, Rona K.
Loubser, Odell
van Raamsdonk, Jeremy
Singaraja, Roshni
Yang, Yu-Zhou
Gafni, Juliette
Bredesen, Dale
Hersch, Steven M.
Leavitt, Blair R.
Roy, Sophie
Nicholson, Donald W.
Hayden, Michael R.
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine (polyQ) expansion in the protein huntingtin (htt). Pathogenesis in HD seems to involve the formation of neuronal intranuclear inclusions and the abnormal regulation of transcription and signal transduction. To identify previously uncharacterized htt-interacting proteins in a simple model system, we used a yeast two-hybrid screen with a Caenorhabditis elegans activation domain library. We found a predicted SH3 domain protein (K08E3.3b) that interacts with N-terminal htt in two-hybrid tests.

Holbert, Sébastien
Dedeoglu, Alpaslan
Humbert, Sandrine
Saudou, Frédéric
Ferrante, Robert J.
Neri, Christian
Publication Title: 
Molecular Biology of the Cell

Increased expression of vascular endothelial growth factor (VEGF) contributes to the growth of many tumors by increasing angiogenesis. Although hypoxia is a potent inducer of VEGF, we previously showed that epidermal growth factor receptor amplification and loss of PTEN, both of which can increase phosphatidylinositol-3-kinase (PI3K) activity, increase VEGF expression.

Pore, Nabendu
Liu, Shuang
Shu, Hui-Kuo
Li, Bin
Haas-Kogan, Daphne
Stokoe, David
Milanini-Mongiat, Julie
Pages, Gilles
O'Rourke, Donald M.
Bernhard, Eric
Maity, Amit
Publication Title: 
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

Huntington's disease (HD) is a fully penetrant autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in the Huntingtin gene. Transcriptional dysfunction, excitotoxicity, and oxidative stress have all been proposed to play important roles in the pathogenesis of HD. This study was designed to explore the therapeutic potential of mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic.

Ferrante, Robert J.
Ryu, Hoon
Kubilus, James K.
D'Mello, Santosh
Sugars, Katharine L.
Lee, Junghee
Lu, Peiyuan
Smith, Karen
Browne, Susan
Beal, M. Flint
Kristal, Bruce S.
Stavrovskaya, Irina G.
Hewett, Sandra
Rubinsztein, David C.
Langley, Brett
Ratan, Rajiv R.
Publication Title: 

The inducible IkappaB kinase (IKKi/IKKepsilon) is a recently described serine-threonine kinase that activates the transcription factors NFkappaB, interferon regulatory factor-3 (IRF3) and CCAAA/enhancer-binding protein (C/EBPdelta). Several inflammatory agents have been shown to induce the expression of the IKKi gene in macrophages and other cell types but the mechanism is unknown.

Wang, Naizhen
Ahmed, Salahuddin
Haqqi, Tariq M.
Publication Title: 
Progress in Neurobiology

Transcriptional dysregulation in Huntington's disease (HD) is a well documented and broadly studied phenomenon. Its basis appears to be in huntingtin's aberrant protein-protein interactions with a variety of transcription factors. The development of therapeutics targeting altered transcription, however, faces serious challenges. No single transcriptional regulator has emerged as a primary actor in HD. The levels of literally hundreds of RNA transcripts are altered in affected cells and it is uncertain which are most relevant.

Kazantsev, Aleksey G.
Hersch, Steven M.
Publication Title: 
PloS One

Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency and striatal degeneration. Copper and iron are increased in the striata of HD patients, but the role of these metals in HD pathogenesis is unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations of copper and iron found in human HD brain are reiterated in the brains of affected HD transgenic mice.

Fox, Jonathan H.
Kama, Jibrin A.
Lieberman, Gregory
Chopra, Raman
Dorsey, Kate
Chopra, Vanita
Volitakis, Irene
Cherny, Robert A.
Bush, Ashley I.
Hersch, Steven
Publication Title: 
American Journal of Physiology. Heart and Circulatory Physiology

Bromelain (Br), a proteolytic enzyme extracted from the stem of the pineapple, is known to possess anti-inflammatory activity and has been shown to reduce blood viscosity, prevent the aggregation of blood platelets, and improve ischemia-reperfusion (I/R) injury in a skeletal muscle model. We investigated the capacity of Br to limit myocardial injury in a global I/R model. Adult male Sprague-Dawley rats were divided into two groups: control (PBS) and Br at 10 mg/kg in PBS administered via intraperitoneal injection (twice/day) for 15 consecutive days.

Juhasz, Bela
Thirunavukkarasu, Mahesh
Pant, Rima
Zhan, Lijun
Penumathsa, Suresh Varma
Secor, Eric R.
Srivastava, Sapna
Raychaudhuri, Utpal
Menon, Venugopal P.
Otani, Hajime
Thrall, Roger S.
Maulik, Nilanjana


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