Faculty Director: Wenzhen Duan, M.D, Ph.D.

Link to PubMed publications for Duan, Wenzhen

Research Direction: Unraveling pathogenic mechanisms to advance novel therapeutic targets and biomarkers for Huntington’s disease

Mutant huntingtin aggregates in zQ175 HD mouse brain. Immunofluorescent staining was performed in the brain sections of zQ175 mice at indicated ages- 6 months (A) and 12 months (B). EM48-positive mutant huntingtin aggregates (red fluorescent signal) and neuronal marker NeuN (green color) were labeled. Scale bar = 200 μm.

Huntington's disease (HD) is a monogenic neurodegenerative disorder that presents with progressive motor, psychiatric, and cognitive symptoms leading to early disability and mortality. Although significant advances have been made in identification of molecular pathways and screening of potential drug targets, a stand-alone therapeutic strategy cannot reverse HD progression and no treatments to slow disease progression exist. The goal of Translational Neurobiology Laboratory is to define key cellular and molecular events leading to neurodegeneration and to advance disease-modifying treatment as well as develop biomarkers to guide therapeutic trials in HD. Our research program is designed to incorporate molecular mechanism studies with animal models to provide a comprehensive understanding of HD pathogenesis, from developmental abnormality to neurodegenerative process. We are illustrating how multifaceted interrogations of basic science and translational neurobiology in the context of HD can reveal new targets and biomarkers for testing mechanism-based intervention.

Building on significant scientific discoveries we have made in the HD fields and technological innovations we have pioneered, our research focus will continue to investigate the molecular bases of mutant huntingtin-mediated neurotoxicity, elucidate how mutant huntingtin levels are regulated, decipher the mechanism whereby defects in the neurovascular-glia crosstalk contribute to neurodegeneration, and develop lipid nanoparticle-formulated gene therapy. Two interlinked research directions are pursued: identifying novel therapeutic targets and investigating mechanisms of neurovascular-glia crosstalk to advance early neuroimaging biomarkers for HD.

Figure legend. Representative in vivo MRI images with deformation-based morphometry (DBM) of relative tissue volume; major structural boundaries defined in the control mouse are overlaid on the R6/2 mouse and color-coded Jacobian maps for visual guidance. In the Jacobian map, only regions with significant change in local tissue volume (false discovery rate = 0.05) are shown. The color reflects the normalized local tissue volume with respect to local tissue volume in similar regions in the control mouse brains. Green and blue in the Jacobian map indicate mild and severe atrophy, respectively. Atrophy in the neocortex (white arrows), striatum (yellow arrows), piriform cortex (magenta arrows), hippocampus (red arrows), thalamus (orange arrows), and amygdala (cyan arrows) can be appreciated (Zhang et al., Neuroimage 2010 49(3):2340-51).

As a part of the Division of Neurobiology, we have established strong collaborations and pioneered in identifying molecular targets to selectively reduce mutant huntingtin levels, revealing new mechanisms to perturbate mutant huntingtin toxicity, and investigating advanced neuroimaging techniques in HD preclinical studies with a coordination to human studies to translate our bench findings to benefit HD patients. Our projects are performed in close collaborations with experts in different fields, including Drs. Christopher Ross and Russell Margolis who are experts in HD research and clinic within Division of Neurobiology, Drs. Michael Miller (Biomedical Engineering) and Susumu Mori (Radiology) who are experts in structural MRI and pioneering cutting-edge technologies in computational neuroimaging analysis, Drs. Jun Hua and Jiadi Xu at the Kennedy Krieger Institute and Drs. Peter van Zijl and Hanzhang Lu at the Department of Radiology for advanced functional neuroimaging studies, Dr. Luo Gu (Material Science) who is an expert in nanotechnology, and Drs. Gene Yeo and Xiangdong Fu at UCSD in developing RNA-targeting gene therapies for HD.

Selected Publications

1. Liu H, Zhang C, Xu J, Jin J, Cheng L, Wu Q, Wei Z, Liu P, Lu H, van Zijl PCM, Ross CA, Hua J, Duan W. HTT silencing delays onset and slows progression of Huntington’s disease like phenotype: Monitoring with a novel neurovascular biomarker. BioRxiv doi: https://doi.org/10.1101/2020.117.386631.
2. Jiang M, Zhang X, Liu H, LeBron J, Alexandris A, Peng Q, Gu H, Yang F, Li Y, Wang R, Hou Z, Arbez N, Ren Q, Dong J, Whela E, Wang R, Ratovitski T, Troncoso JC, Mori S, Ross CA, Lim J, Duan W. Nemo-like Kinase Reduces Mutant Huntingtin Levels and Mitigates Huntington’s Disease. Hum Mol Genet, 2020 .
3. Zhang C, Wu Q, Liu H, Cheng L, Hou Z, Mori S, Hua J, Ross CA, Zhang J, Nopoulos PC, Duan W. Abnormal brain development in Huntington’ disease is recapitulated in the zQ175 knock-in mouse model. Cerebral Cortex Communications, 2020;1(1):tgaa044. doi: 10.1093/texcom/tgaa044.
4. Zhou X, Li G, Kaplan A, Gaschler MM, Zhang X, Hou Z, Jiang M, Zott R, Cermers S, Stockwell BR, Duan W. Small molecule modulator of protein disulfide isomerase attenuates mutant huntingtin toxicity and inhibits endoplasmic reticulum stress in a mouse model of Huntington's disease. Hum Mol Gen 2018, May 1, 27(9):1545-1555.
5. Li Q, Li G, Wu D, Lu H, Hou Z, Ross CA, Yang Y, Zhang J, Duan W. Resting-state functional MRI reveals altered brain connectivity and its correlation with motor dysfunction in a mouse model of Huntington’s disease. Sci Rep 2017, Dec 1; 7(1):16742.
6. Wu B, Jiang M, Peng Q, Li G, Hou Z, Milne GL, Mori S, Alonso R, Geisler JG, Duan W. 2,4 DNP improves motor function, preserves medium spiny neuronal identity, and reduces oxidative stress in a mouse model of Huntington's disease. Exp Neurol 2017, Mar 28, 293:83-90 (In phase I clinical trial).
7. Jin J, Gu H, Anders NM, Ren T, Jiang M, Tao M, Peng Q, Rudek MA, Duan W. Metformin protects cells from mutant huntingtin toxicity through activation of AMPK and modulation of mitochondrial dynamics. NeuroMolecular Medicine, 2016 Dec; 18(4):581-592.
8. Jin J, Peng Q, Hou Z, Jiang M, Wang X, Langseth AJ, Tao M, Barker PB, Mori S, Bergles DE, Ross CA, Detloff PJ, Zhang J, Duan W. Early white matter abnormalities, progressive brain pathology and motor deficits in a novel knock-in mouse model of Huntington’s disease. Hum Mol Genet 2015, 24(9):2508-2527.
9. Jiang M, Zheng J, Peng Q, Hou Z, Zhang J, Mori S, Ellis JL, Vlasuk GP, Fries H, Suri V, Duan W. Sirtuin 1 activator SRT2104 protects Huntington’s disease mice. Annals of Clinical and Translational Neurology 2014, 1(12):1047-1052.
10. Jiang M, Peng Q, Liu X, Jin J, Hou Z, Zhang J, Mori S, Ross CA, Ye K and Duan W. Small molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington’s disease. Hum Mol Genet 2013, 22(12):2462-2470.
11. Fu J, Jin J, Cichewicz RH, Hageman SA, Ellis TK, Xiang L, Peng Q, Jiang M, Arbez N, Hotaling K, Ross CA and Duan W. Trans-(-)-ε-viniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMPK, and protects cells in models of Huntington’s disease. J Bio Chem, 2012, 287(29):24460-72.
12. Jiang M, Wang J, Fu J, Du L, Jeong H, West T, Xiang L, Peng Q, Hou Z, Cai H, Seredenin T, Arbez N, Zhu S, Sommers K, Qian J, Zhang J, Mori S, Yang XW, Tamashiro KLK, Aja S, Moran TH, Luthi-Carter R, Martin B, Maudsley S, Mattson MP, Cichewicz RH, Ross CA, Holtzman DM, Krainc D, Duan W. Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nature Medicine, 2012, 18(1): 153-158.
13. Cheng Y, Peng Q, Hou Z, Aggarwal M, Zhang J, Mori S, Ross CA, Duan W. Structural MRI detects progressive regional brain atrophy and neuroprotective effects in N171-82Q Huntington’s disease mouse model. Neuroimage, 2011, 56:1027-1034.
14. Jiang M, Porat-Shliom Y, Pei Z, Cheng Y, Xiang L, Sommers K, Li Q, Gillardon F, Hengerer B, Berlinicke C, Smith WW, Zack D, Poirier MA, Ross CA, Duan W. Baicalein reduces E46K alpha-synuclein aggregation in vitro and protects cells against E46K alpha-synuclein toxicity in cell models of familiar Parkinsonism. J Neurochem, 2010, 114(2):419-29.
15. Zhang J, Peng Q, Li Q, Jahanshad N, Hou Z, Jiang M, Masuda N, Langbehn DR, Miller MI, Mori S, Ross CA, Duan W. Longitudinal characterization of brain atrophy of a Huntington’s disease mouse model by automated morphological analyses of magnetic resonance images. Neuroimage, 2010, 49(3):2340-51.