How has DISCI enabled drug discovery?

被引:30
作者
Wang, Qi [1 ]
Jaaro-Peled, Hanna [2 ]
Sawa, Akira [2 ,3 ,4 ]
Brandon, Nicholas J. [1 ]
机构
[1] Wyeth Ayerst Res, Discovery Neurosci, Princeton, NJ 08543 USA
[2] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD USA
关键词
DISC1; psychiatric disorders; schizophrenia; PDE4; nudel/ndell; animal models;
D O I
10.1016/j.mcn.2007.10.006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Growing genetic and clinical evidence has shown that disrupted-in-schizophrenia 1 (DISC1) is one of the most compelling risk genes for schizophrenia and other major mental disorders. The understanding of the role that DISC1 plays in neuronal development and cell signaling has been greatly enhanced by the identification of DISC1 binding partners, an appreciation of its expression during development and functional studies using RNA interference. But what is the impact of this explosion of data for psychiatric drug discovery? Though we are at a very early stage of our understanding of DISC1 biology, it is an important time to review what has already been achieved and to discuss its impact. DISC1 biology has enabled the identification of new therapeutic targets in the form of DISC1 binding partners and other molecules found within a large DISC1 interaction network, the so-called 'DISC1 interactome'. We will review the better characterized of these interactions and also emphasize the richness of potential targets in the more poorly studied areas of the interactome. Furthermore, DISC1 has encouraged the development of new animal models for psychiatric disorders, which is critical for the study of disease biology. Thus, DISC1 may have the potential to not only point us in the direction of novel drug targets but also provide more relevant animal models for compound testing. (C) 2007 Elsevier Inc. All rights reserved.
引用
收藏
页码:187 / 195
页数:9
相关论文
共 83 条
[1]   DISC1 (Disrupted in Schizophrenia-1) is expressed in limbic regions of the primate brain [J].
Austin, CP ;
Ma, L ;
Ky, B ;
Morris, JA ;
Shughrue, PJ .
NEUROREPORT, 2003, 14 (07) :951-954
[2]   Schizophrenia and affective disorders - Cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: Clinical and P300 findings in a family [J].
Blackwood, DHR ;
Fordyce, A ;
Walker, MT ;
St Clair, DM ;
Porteous, DJ ;
Muir, WJ .
AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 69 (02) :428-433
[3]   Primate disrupted-in-schizophrenia-1 (DISC1): High divergence of a gene for major mental illnesses in recent evolutionary history [J].
Bord, Lyuda ;
Wheeler, Jeff ;
Paek, Matthew ;
Saleh, Masoumeh ;
Lyons-Warren, Ariel ;
Ross, Christopher A. ;
Sawamura, Naoya ;
Sawa, Akira .
NEUROSCIENCE RESEARCH, 2006, 56 (03) :286-293
[4]   Neurotensin agonists - Potential in the treatment of schizophrenia [J].
Boules, Mona ;
Shaw, Amanda ;
Fredrickson, Paul ;
Richelson, Elliott .
CNS DRUGS, 2007, 21 (01) :13-23
[5]   Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders [J].
Brandon, NJ ;
Handford, EJ ;
Schurov, I ;
Rain, JC ;
Pelling, M ;
Duran-Jimeniz, B ;
Camargo, LM ;
Oliver, KR ;
Beher, D ;
Shearman, MS ;
Whiting, PJ .
MOLECULAR AND CELLULAR NEUROSCIENCE, 2004, 25 (01) :42-55
[6]  
BRANDON NJ, ANN REP MED CHEM
[7]   Thiol-dependent cathepsins:: Pathophysiological implications and recent advances in inhibitor design [J].
Brömme, D ;
Kaleta, J .
CURRENT PHARMACEUTICAL DESIGN, 2002, 8 (18) :1639-1658
[8]   DISC1 and neurocognitive function in schizophrenia [J].
Burdick, KE ;
Hodgkinson, CA ;
Szeszko, PR ;
Lencz, T ;
Ekholm, JM ;
Kane, JM ;
Goldman, D ;
Malhotra, AK .
NEUROREPORT, 2005, 16 (12) :1399-1402
[9]  
BURGIN KE, 1990, J NEUROSCI, V10, P1788
[10]  
Byk T, 1996, J NEUROSCI, V16, P688