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    Zuoshang Xu MD, PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentBiochemistry and Molecular Pharmacology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-3309
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentCell and Developmental Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCell Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentTranslational Science

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCenter for AIDS Research

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentProgram in Cell Dynamics

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentRNA Therapeutics Institute

        Overview 
        Narrative

        Mechanism and therapy of neurodegenerative diseases

        Zoushang Xu, Ph.D.My laboratory is working to understand the mechanism of neurodegeneration in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). ALS causes motor neuron degeneration, paralysis and death. FTD causes neurodegeneration in frontal and temporal cortex, resulting in degeneration of high brain functions, including altered personality, loss of executive ability, disabled social functions and regressive language skills. ALS and FTD are related because sometimes both diseases occur in the same patients and they share some cellular pathological features. We study these diseases by generating and analyzing animal models for these diseases. We are also developing RNAi therapy for these diseases.

        We generate and use two types of animal models. One is gene overexpression models and the other is gene knockdown models. One overexpression model that we study is mice that express mutant human copper, zinc superoxide dismutase (SOD1) gene, which causes ALS. These mice develop ALS symptoms similar to humans. We hypothesize that mitochondrial damage and chaperone dysfunction contributes to motor neuron degeneration caused by mutant SOD1. Our experimental data support this hypothesis (Xu et al., 2004; Tummala et al., 2005). In addition to these mechanistic studies, we also use these mice to test new RNAi therapy strategies (Ding et al., 2003; Schwarz et al., 2006; Xia et al., 2006a).

        For gene knockdown models, we use transgenic RNAi method that we have developed. We have demonstrated that transgenic RNAi knockdown of specific genes can recapitulate gene knockout phenotypes (Xia et al., 2006b). We have used transgenic RNAi to demonstrate that allele-specific silencing works in vivo (Xia et al., 2006a). Recently we have developed more sophisticated conditional knockdown strategies so that gene knockdown can be controlled spatially and temporally. We are using this transgenic RNAi strategy to target genes that are involved in ALS, FTD and Alzhermer’s disease.

        In developing RNAi therapy strategies, we are testing two approaches. One is to express RNAi using viral vectors to silence disease genes. The other approach is being conducted in collaboration with Dr. Tariq Rana’s lab. We are testing delivering RNAi therapy using chemically modified siRNA that has enhanced stability. By these approaches, we hope that we will bring RNAi to clinical application for treatment of neurodegenerative diseases as well as other CNS disorders.



        Post Docs

        One postdoctoral position is available to study the mechanism and treatment of motor neuron disease. Experience in molecular biology and neuroscience is preferred. Contact Dr. Xu for additional details.

        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Zuoshang Xu Chunxing Yang. TDP-43 The key to understanding amyotrophic lateral sclerosis. Rare Diseases. 2014.
        2. Yang B, Li S, Wang H, Guo Y, Gessler DJ, Cao C, Su Q, Kramer J, Zhong L, Ahmed SS, Zhang H, He R, Desrosiers RC, Brown R, Xu Z, Gao G. Global CNS Transduction of Adult Mice by Intravenously Delivered rAAVrh.8 and rAAVrh.10 and Nonhuman Primates by rAAVrh.10. Mol Ther. 2014 Jul; 22(7):1299-309.
          View in: PubMed
        3. Yang C, Wang H, Qiao T, Yang B, Aliaga L, Qiu L, Tan W, Salameh J, McKenna-Yasek DM, Smith T, Peng L, Moore MJ, Brown RH, Cai H, Xu Z. Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2014 Mar 25; 111(12):E1121-9.
          View in: PubMed
        4. Cheng W, Ip YT, Xu Z. Gudu, an Armadillo repeat-containing protein, is required for spermatogenesis in Drosophila. Gene. 2013 Dec 1; 531(2):294-300.
          View in: PubMed
        5. Broering TJ, Wang H, Boatright NK, Wang Y, Baptista K, Shayan G, Garrity KA, Kayatekin C, Bosco DA, Matthews CR, Ambrosino DM, Xu Z, Babcock GJ. Identification of human monoclonal antibodies specific for human SOD1 recognizing distinct epitopes and forms of SOD1. PLoS One. 2013; 8(4):e61210.
          View in: PubMed
        6. Qiu L, Qiao T, Beers M, Tan W, Wang H, Yang B, Xu Z. Widespread aggregation of mutant VAPB associated with ALS does not cause motor neuron degeneration or modulate mutant SOD1 aggregation and toxicity in mice. Mol Neurodegener. 2013; 8:1.
          View in: PubMed
        7. Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, Lowe P, Koppers M, McKenna-Yasek D, Baron DM, Kost JE, Gonzalez-Perez P, Fox AD, Adams J, Taroni F, Tiloca C, Leclerc AL, Chafe SC, Mangroo D, Moore MJ, Zitzewitz JA, Xu ZS, van den Berg LH, Glass JD, Siciliano G, Cirulli ET, Goldstein DB, Salachas F, Meininger V, Rossoll W, Ratti A, Gellera C, Bosco DA, Bassell GJ, Silani V, Drory VE, Brown RH, Landers JE. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012 Aug 23; 488(7412):499-503.
          View in: PubMed
        8. Xu ZS. Does a loss of TDP-43 function cause neurodegeneration? Mol Neurodegener. 2012; 7:27.
          View in: PubMed
        9. Zhang H, Yang B, Mu X, Ahmed SS, Su Q, He R, Wang H, Mueller C, Sena-Esteves M, Brown R, Xu Z, Gao G. Several rAAV vectors efficiently cross the blood-brain barrier and transduce neurons and astrocytes in the neonatal mouse central nervous system. Mol Ther. 2011 Aug; 19(8):1440-8.
          View in: PubMed
        10. Qiu L, Rivera-Pérez JA, Xu Z. A non-specific effect associated with conditional transgene expression based on Cre-loxP strategy in mice. PLoS One. 2011; 6(5):e18778.
          View in: PubMed
        11. Yang C, Qiu L, Xu Z. Specific gene silencing using RNAi in cell culture. Methods Mol Biol. 2011; 793:457-77.
          View in: PubMed
        12. Yang C, Tan W, Whittle C, Qiu L, Cao L, Akbarian S, Xu Z. The C-terminal TDP-43 fragments have a high aggregation propensity and harm neurons by a dominant-negative mechanism. PLoS One. 2010; 5(12):e15878.
          View in: PubMed
        13. Wu R, Wang H, Xia X, Zhou H, Liu C, Castro M, Xu Z. Nerve injection of viral vectors efficiently transfers transgenes into motor neurons and delivers RNAi therapy against ALS. Antioxid Redox Signal. 2009 Jul; 11(7):1523-34.
          View in: PubMed
        14. Qiu L, Wang H, Xia X, Zhou H, Xu Z. A construct with fluorescent indicators for conditional expression of miRNA. BMC Biotechnol. 2008; 8:77.
          View in: PubMed
        15. Wang H, Ghosh A, Baigude H, Yang CS, Qiu L, Xia X, Zhou H, Rana TM, Xu Z. Therapeutic gene silencing delivered by a chemically modified small interfering RNA against mutant SOD1 slows amyotrophic lateral sclerosis progression. J Biol Chem. 2008 Jun 6; 283(23):15845-52.
          View in: PubMed
        16. Zou T, Ilangovan R, Yu F, Xu Z, Zhou J. SMN protects cells against mutant SOD1 toxicity by increasing chaperone activity. Biochem Biophys Res Commun. 2007 Dec 28; 364(4):850-5.
          View in: PubMed
        17. Schwarz DS, Ding H, Kennington L, Moore JT, Schelter J, Burchard J, Linsley PS, Aronin N, Xu Z, Zamore PD. Designing siRNA that distinguish between genes that differ by a single nucleotide. PLoS Genet. 2006 Sep 8; 2(9):e140.
          View in: PubMed
        18. Xia X, Zhou H, Huang Y, Xu Z. Allele-specific RNAi selectively silences mutant SOD1 and achieves significant therapeutic benefit in vivo. Neurobiol Dis. 2006 Sep; 23(3):578-86.
          View in: PubMed
        19. Xia XG, Zhou H, Xu Z. Multiple shRNAs expressed by an inducible pol II promoter can knock down the expression of multiple target genes. Biotechniques. 2006 Jul; 41(1):64-8.
          View in: PubMed
        20. Xia XG, Zhou H, Xu Z. Transgenic RNAi: Accelerating and expanding reverse genetics in mammals. Transgenic Res. 2006 Jun; 15(3):271-5.
          View in: PubMed
        21. Schonhoff CM, Matsuoka M, Tummala H, Johnson MA, Estevéz AG, Wu R, Kamaid A, Ricart KC, Hashimoto Y, Gaston B, Macdonald TL, Xu Z, Mannick JB. S-nitrosothiol depletion in amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2006 Feb 14; 103(7):2404-9.
          View in: PubMed
        22. Xia XG, Zhou H, Samper E, Melov S, Xu Z. Pol II-expressed shRNA knocks down Sod2 gene expression and causes phenotypes of the gene knockout in mice. PLoS Genet. 2006 Jan; 2(1):e10.
          View in: PubMed
        23. Tiwari A, Xu Z, Hayward LJ. Aberrantly increased hydrophobicity shared by mutants of Cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosis. J Biol Chem. 2005 Aug 19; 280(33):29771-9.
          View in: PubMed
        24. Zhou H, Xia XG, Xu Z. An RNA polymerase II construct synthesizes short-hairpin RNA with a quantitative indicator and mediates highly efficient RNAi. Nucleic Acids Res. 2005; 33(6):e62.
          View in: PubMed
        25. Tummala H, Jung C, Tiwari A, Higgins CM, Hayward LJ, Xu Z. Inhibition of chaperone activity is a shared property of several Cu,Zn-superoxide dismutase mutants that cause amyotrophic lateral sclerosis. J Biol Chem. 2005 May 6; 280(18):17725-31.
          View in: PubMed
        26. Xia XG, Zhou H, Zhou S, Yu Y, Wu R, Xu Z. An RNAi strategy for treatment of amyotrophic lateral sclerosis caused by mutant Cu,Zn superoxide dismutase. J Neurochem. 2005 Jan; 92(2):362-7.
          View in: PubMed
        27. Xia XG, Zhou H, Xu Z. Promises and challenges in developing RNAi as a research tool and therapy for neurodegenerative diseases. Neurodegener Dis. 2005; 2(3-4):220-31.
          View in: PubMed
        28. Xu Z, Jung C, Higgins C, Levine J, Kong J. Mitochondrial degeneration in amyotrophic lateral sclerosis. J Bioenerg Biomembr. 2004 Aug; 36(4):395-9.
          View in: PubMed
        29. Schwarz DS, Hutvágner G, Du T, Xu Z, Aronin N, Zamore PD. Asymmetry in the assembly of the RNAi enzyme complex. Cell. 2003 Oct 17; 115(2):199-208.
          View in: PubMed
        30. Xia XG, Zhou H, Ding H, Affar el B, Shi Y, Xu Z. An enhanced U6 promoter for synthesis of short hairpin RNA. Nucleic Acids Res. 2003 Sep 1; 31(17):e100.
          View in: PubMed
        31. Ding H, Schwarz DS, Keene A, Affar el B, Fenton L, Xia X, Shi Y, Zamore PD, Xu Z. Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis. Aging Cell. 2003 Aug; 2(4):209-17.
          View in: PubMed
        32. Higgins CM, Jung C, Xu Z. ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes. BMC Neurosci. 2003 Jul 15; 4:16.
          View in: PubMed
        33. Jung C, Higgins CM, Xu Z. Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis. J Neurochem. 2002 Nov; 83(3):535-45.
          View in: PubMed
        34. Zhang Z, Casey DM, Julien JP, Xu Z. Normal dendritic arborization in spinal motoneurons requires neurofilament subunit L. J Comp Neurol. 2002 Aug 19; 450(2):144-52.
          View in: PubMed
        35. Jung C, Higgins CM, Xu Z. A quantitative histochemical assay for activities of mitochondrial electron transport chain complexes in mouse spinal cord sections. J Neurosci Methods. 2002 Mar 15; 114(2):165-72.
          View in: PubMed
        36. Higgins CM, Jung C, Ding H, Xu Z. Mutant Cu, Zn superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNS. J Neurosci. 2002 Mar 15; 22(6):RC215.
          View in: PubMed
        37. Xu Z, Tung VW. Temporal and spatial variations in slow axonal transport velocity along peripheral motoneuron axons. Neuroscience. 2001; 102(1):193-200.
          View in: PubMed
        38. Xu Z. Mechanism and treatment of motoneuron degeneration in ALS: what have SOD1 mutants told us? Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Sep; 1(4):225-34.
          View in: PubMed
        39. Xu Z, Tung VW. Overexpression of neurofilament subunit M accelerates axonal transport of neurofilaments. Brain Res. 2000 Jun 2; 866(1-2):326-32.
          View in: PubMed
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