Postdoctoral Position Available

Zuoshang Xu, Ph.D.,M.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Biochemistry and Molecular Pharmacology

Other Affiliation(s):
   Cell Biology
   Cell Dynamics Group
   Center for AIDS Research
   Interdisciplinary Graduate Program
   Program in Neuroscience

Mechanism and therapy of neurodegenerative diseases

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.

Representative Publications

Qiu L, Wang H, Xia X, Zhou H, Xu Z.  A construct with fluorescent indicators for conditional expression of miRNA. BMC Biotechnol. 2008 Oct 7;8:77.

Wu R, Wang H, Xia XG, Zhou H, Liu C, Castro MG, Xu Z.  Nerve injection of viral vectors efficiently transfers transgenes into motor neurons and delivers RNAi therapy against ALS. Antioxid Redox Signal. 2009 Apr 3.

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. Epub 2008 Mar 26.

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. Epub 2006 Jan 27

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 Jul 18; [Epub ahead of print]

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

Schwarz DS, Ding H, Kennington L, Moore JT, Schelter J, Burchard J, Linsley PS, Aronin N, Xu Z, Zamore PD.  (2006).   Designing siRNA That Distinguish between Genes That Differ by a Single Nucleotide .  PLoS Genet. 2006 Sep 8;2(9) [Epub ahead of print]

Xu Z, Zhou H and Xia, XG (2006) Reverse Genetics in Mammals using RNAi.  Cellscience 3(1): http://www.cellscience.com/reviews9/Reverse_Genetics_RNAi.html

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

Xu Z, Xia XG.   RNAi therapy: Dominant disease gene gets silenced .  Gene Ther  2005 Aug;12(15):1159-60

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 Jun 15     

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    

Manfredi G, Xu Z.    Mitochondrial dysfunction and its role in motor neuron degeneration in ALS .  Mitochondrion. 2005 Apr;5(2):77-87

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 Apr 1;33(6):e62.

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.

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.

Schwarz DS, Hutvagner 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.

Xia XG, Zhou HX, Ding HL, Affar EB, Shi Y, Xu ZS (2003)  An enhanced U6 promoter for synthesis of small hairpin RNA.  Nuc Acids Res, e100 (pp1-5).

Ding HL, Schwarz DS, Keene A, Affar E, Fenton L, Xia XG, Shi Y, Zamore PD and Xu ZS (2003)  Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis.  Aging Cell 2: 209-217.

Higgins CJM, Jung, CW, Xu ZS (2003)  ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and involvement of peroxisomes . BMC Neuroscience 4: 16 (pp1-14).

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.

Higgins CJM, Jung C, Ding HL and Xu ZS (2002)  Mutant Cu, Zn superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the central nervous system.  J Neurosci 22: RC215, pp1-6.

Jung C, Higgins CJM and Xu ZS (2002)  Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis .   J Neurochem 83: 535-45.

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.

Xu ZS and Tung V (2001)  Temporal and spatial variations in slow axonal transport velocity along peripheral motoneuron axons.  Neuroscience 102: 193-200. 

Jung C and Xu Z (2000)  Measuring Quantity and Activity of Mitochondrial Electron Transport Chain (ETC) Complexes in Nervous Tissues Using BN-PAGE .   Anal Biochem 286: 214-23.

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.

Xu Z and Tung V (2000)  Overexpression of neurofilament subunit M accelerates neurofilament transport. Brain Res   866: 326-32.

Levine J, Kong J-M, Nadler M. and Xu Z-S (1999)  Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS). Glia, 28: 215-224.

Kong J-M and Xu Z (1999)  Peripheral Axotomy Slows Motor Neuron Degeneration in a Transgenic Mouse Line Expressing Mutant SOD1 G93A .   J Comp Neurol 412:373-80.

Kong, J-M and Xu, Z-S (1998).  Mitochondrial vacuolation is an initial event in triggering ALS in mutant SOD1 transgenic mice .   J Neurosci, 18: 3241-325

Kong J-M, Tung V, Aghjanian J and Xu Z-S (1998). Antagonistic roles between neurofilament subunits NF-H/NF-M and NF-L in shaping dendritic arborization in spinal cord motor neurons .   J Cell Biol. 140: 1167-76.

Laboratory Staff

Postdoctoral fellows: Hongliu Ding, Xugang Xia, Hongxia Zhou, and Hongyan Wang

Research Associates:  Ellen Trang, Michael Gershenovich, and Yingping Yu

Office: NRB 817, 870 L-N
Phone: 508-856-3309
E-mail: Zuoshang.Xu@umassmed.edu

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Postdoctoral Position Available 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.