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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 Aβ in the brain is a central pathological feature of AD. Aβ 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 Aβ, or a 42 amino acid form of Aβ 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: α, β and γ-secretase. In normal condition, a majority of APP is cleaved by α-secretase within the Aβ domain to generate secreted form of APP (sAPP α) and a smaller 83-residue C-terminal fragment (C83 or CTFα), and it precludes Aβ generation. Aβ is generated from APP by β-secretase (BACE1) and γ-secretase. APP is cleaved by BACE1 to generate a secreted form of APP (sAPPβ) and a 99-residue membrane-associated fragment (C99). C99 is the substrate of γ-secretase and intramembrane cleavage at the γ site generates Aβ and CTFγ fragments. Using knockout and transgenic models, we have demonstrated that presenilins are absolutely required for γ-secretase cleavage of APP to generate Aβ 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 S, Zhang S, Bromley-Brits K, Cai F, Zhou W, Xia K, Mittelholtz J, Song W. (2011). Transcriptional regulation of TMP21 by NFAT. Molecular Neurodegeneration 6, 21. Chen CH, Zhou W, Liu S, Deng Y, Cai F, Tone M, Tone Y, Tong Y, Song W. (2011). Increased NF-κB signaling upregulates BACE1 expression and its therapeutic potential in Alzheimer's disease.
International Journal of Neuropsychopharmacology Sun X, Wu Y, Chen B, Zhang Z, Zhou W, Tong Y, Yuan J, Xia K, Gronemeyer H, Flavell RA, Song W. (2011). Regulator of calcineurin 1 (RCAN1) facilitates neuronal apoptosis through caspase 3 activation. Journal of Biological Chemistry 286, 9049-9062. Wang R, Zhang M, Zhou W, Ly PT,
Cai F, Song W (2011). NF-κB signaling inhibits ubiquitin
carboxyl-terminal hydrolase L1 gene expression. Chen B, Bromley-Brits K, He G, Cai F, Zhang X, Song W. (2010). Effect of synthetic cannabinoid HU210 on memory deficits and neuropathology in Alzheimer's disease mouse model. Current Alzheimer Research 7, 255-261. Zhou W, Cai F, Li Y, Yang GS, O'Connor KD, Holt RA, Song W. (2010). BACE1 gene promoter single-nucleotide polymorphisms in Alzheimer's disease. 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, 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 inhibitory factor (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 Aβ 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. 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 of the USA 103, 18727-18732. Sun X, He G, and Song W (2006). BACE2, as a novel APP θ-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome. 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. He G, Qing H, Cai F, Kwok C, Xu H, Yu G, Bernstein A, and Song W (2006). 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. 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. Tong Y, Zhou W, Fung V, Christensen MA, Qing H, Sun X, and Song W (2005). Christensen MA, Zhou W, Qing H, Lehman A, Philipsen S, and Song W. (2004). Transcriptional regulation of BACE1, the β-amyloid precursor protein β-secretase, by Sp1. Qing H, Zhou W, Christensen MA, Sun X, Tong Y, and Song W. (2004) Degradation of BACE by the ubiquitin-proteasome pathway. The FASEB Journal 18(13):1571-3. Zhou W, Qing H, Tong Y, and Song W. (2004) BACE1 gene expression and protein degradation. Annals of the New York Academy of Sciences 1035:49-67. Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA. (2002) Dopamine-dependent neurotoxicity of α-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. 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. Zhang, Z., Nadeau, P., Song, W.,Yuan, M., Donoviel, D., Bernstein, A., and Yankner, B.A. (2000) Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1. Nature Cell Biology 2, 463-465. Song, W., Nadeau, P., Yuan, M., Yang, X., Shen, J. and Yankner, B.A. (1999) Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Song W, Lahiri DK. (1995) Efficient transfection of DNA by mixing cells in suspension with calcium phosphate. Nucleic Acids Research 23(17):3609-11.
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