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| About My Lab | |
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DR. WEIHONG SONG
My laboratory focuses on the molecular and cellular mechanism of Alzheimer s Disease (AD) pathogenesis. Alzheimer s disease is the most common neurodegenerative disorder leading to dementia. It accounts for two-thirds of all cases of dementia and its prevalence increases with age. AD affects about 10% of the population over the age of 65. Deposition of Ab in the brain is a central pathological feature of AD. Ab is derived from APP, a type 1 transmembrane protein. Recent molecular genetic studies have shown that four genes confer susceptibility to AD: APP gene on chromosome 21; Apo E gene on chromosome 19; Presenilin 1 (PS1) on chromosome 14; and Presenilin 2 (PS2) on chromosome 1. Autosomal dominant inheritance of AD can arise from mutations of APP or PS1 and PS2. These mutations alter the processing of APP giving rise to increased production of Ab, or a 42 amino acid form of Ab with a high propensity for plaque formation, implicating a role for altered APP processing in the pathogenesis of familial AD.
APP undergoes a complex set of proteolytic processing by three different enzymes: a, b and g-secretase. In normal condition, a majority of APP is cleaved by a-secretase within the Ab domain to generate secreted form of APP (sAPPa) and a smaller 83-residue C-terminal fragment (C83 or CTFa), and it precludes Ab generation. Ab is generated from APP by b-secretase (BACE1) and g-secretase. APP is cleaved by BACE1 to generate a secreted form of APP (sAPPb) and a 99-residue membrane-associated fragment (C99). C99 is the substrate of g-secretase and intramembrane cleavage at the g site generates Ab and CTFg fragments.
Using knockout and transgenic models, we have demonstrated that presenilins are absolutely required for g-secretase cleavage of APP to generate Ab and intramembrane cleavage of Notch to generate NICD. Our lab recently found that SP1 playes an important role in BACE1 gene transcription, and BACE1 is degraded by ubiquitin- proteasome pathway. My laboratory is currently working on projects to further define the role of presenilins and BACE, transcriptional regulation and Notch signal transduction in neurodegeneration. Another research area of laboratory is the molecular genetics of mental disorders.
Member of Editorial Board:
Journal of Clinical Investigation Frontiers in Molecular Neuroscience Journal of Molecular Neuroscience
Selected Publications:
Liu, H., Wang, P., Song, W. and Sun, X. (2009). Degradation of Regulator of Calcineurin 1 (RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways. The FASEB Journal 23(10):3383-3392. Wang, L., Zis, O., Ma, G., Shan, S., Zhang, X., Wang, S., Dai, C., Zhao, J., Lin, Q., Lin, S., and Song, W. (2009). Upregulation of macrophage migration inhibitoryfactor (MIF) gene expression in stroke. Stroke 40, 973-976. Qing, H., He, G., Ly, P.T.T., Christopher J. Fox, C.J., Staufenbiel, M.,Cai, F., Zhang, Z., Wei, S., Sun, X., Chen, C-H., Zhou, W., Wang, K., andSong, W. (2008). Valproic acid inhibits Aß production, neuritic plaque formation and behavioral deficits in Alzheimer's Disease mouse models. The Journal of Experimental Medicine 205, 2781-2789. Liu, S., Bromley-Brits, K., Kun, X., Mittelholtz, J., Wang, R. and Song, W. (2008). TMP21 degradation is mediated by the ubiquitin proteasome pathway. European Journal of Neuroscience 28, 1980-1988. Cai F, Chen B, Zhou W, Zis O, Liu S, Holt RA, Honer WG, and Song W (2008). SP1 regulates the human SNAP-25 gene expression. Journal of Neurochemistry 105, 512-523. He G, Qing H, Ton Y, Cai F, Ishiura S, and Song W (2007). Degradation of Nicastrin involves both proteasome and lysosome. Journal of Neurochemistry 101, 982-992 Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, and Song W (2006). Hypoxia facilitates Alzheimer's Disease pathogenesis by upregulating BACE1 gene expression. Proceedings of National Academy of Sciences, USA 103, 18727-18732. Sun X, He G, and Song W (2006). BACE2, as a novel APP &952;-secretase, is not responsible for the pathogenesis of Alzheimer's Disease in Down Syndrome. The FASEB Journal 20(9):1369-1376. Sun X, Tong Y, Qing, H. Chen C-H, and Song W (2006). Increased BACE1 Maturation contributes to the pathogenesis of Alzheimer's Disease in Down Syndrome. The FASEB Journal 20(9):1361-1368 He G, Qing H, Cai F, Kwok C, Xu H, Yu G, Bernstein A, and Song W (2006). Ubiquitin-proteasome pathway mediates degradation of APH-1. Journal of Neurochemistry 99, 1403-12. Zhou W, and Song W (2006). Leaky scanning and reinitiation regulate BACE1 gene expression. Molecular and Cellular Biology 26(9): 3353-64. Li Y, Zhou W, Tong Y, He G, and Song W (2006). Control of APP Processing and Aß Generation Level by BACE1 Enzymatic Activity and Transcription. The FASEB Journal 20(2):285-92. Sun X, Wang Y, Qing H, Christensen MA, Liu Y, Zhou W, Tong Y, Xiao C, Huang Y, Zhang S, Liu X, and Song W. (2005) Distinct Transcriptional Regulation and Function of The Human BACE2 and BACE1 Genes. The FASEB Journal 19(7):739-749. Song, W., and Yankner, B.A. (2001) Presenilins and Notch Signaling Pathway. In: Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics, Iqbal, K., Sisodia, S.S. & Winbald, B. (eds), Chapter 49, 531-539.
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