Research Topics
Genomes and Genes | Z XuSummaryAffiliation: University of Massachusetts Medical School Country: USA Publications
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Publications
Does a loss of TDP-43 function cause neurodegeneration?Zuo Shang Xu
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, 817 LRB, Worcester, MA 01605, USA
Mol Neurodegener 7:27. 2012....
ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomesCynthia M J Higgins
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, MA 01655, USA
BMC Neurosci 4:16. 2003..To determine which of these possibilities are true, we examined the vacuolar patterns in detail in transgenic mice expressing mutant SOD1G93A...- A construct with fluorescent indicators for conditional expression of miRNALinghua Qiu
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, MA 01605, USA
BMC Biotechnol 8:77. 2008..Furthermore, because microRNA (miRNA) targeting specific genes can be expressed simultaneously with protein coding genes, incorporation of fluorescent marker proteins can simplify the screening and analysis of transgenic RNAi animals... - An RNA polymerase II construct synthesizes short-hairpin RNA with a quantitative indicator and mediates highly efficient RNAiHongxia Zhou
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School 364 Plantation Street, Worcester, MA 01605, USA
Nucleic Acids Res 33:e62. 2005..This system may be adapted for in vivo shRNA expression and gene silencing... 
Mitochondrial degeneration in amyotrophic lateral sclerosisZuoshang Xu
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, Massachusetts 01605, USA
J Bioenerg Biomembr 36:395-9. 2004..Thus, this appears to be a new form of mitochondrial vacuolation and we term this as mitochondrial vacuolation by intermembrane space expansion or MVISE...- Mechanism and treatment of motoneuron degeneration in ALS: what have SOD1 mutants told us?Z Xu
Department of Pharmacology, University of Massachusetts Medical School, Worcester 01655, USA
Amyotroph Lateral Scler Other Motor Neuron Disord 1:225-34. 2000.... - Overexpression of neurofilament subunit M accelerates axonal transport of neurofilamentsZ Xu
Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
Brain Res 866:326-32. 2000.... - Temporal and spatial variations in slow axonal transport velocity along peripheral motoneuron axonsZ Xu
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Neuroscience 102:193-200. 2001..These differences provide a basis for the regional deficiencies in axonal transport associated with several neurological disorders... - Overexpression of neurofilament subunit NF-L and NF-H extends survival of a mouse model for amyotrophic lateral sclerosisJ Kong
Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical School, Worcester 01655, USA
Neurosci Lett 281:72-4. 2000..These results illustrate a beneficial role of neurofilaments in ALS and call into question of several hypotheses regarding the role of neurofilaments in the development of ALS... - Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosisHongliu Ding
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, MA 01605-2324, USA
Aging Cell 2:209-17. 2003..Thus, RNAi is a promising therapy for ALS and other disorders caused by dominant, gain-of-function gene mutations... - Mutant Cu, Zn superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNSCynthia M J Higgins
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA
J Neurosci 22:RC215. 2002..By immunoelectron microscopy, we show that SOD1 is present within mitochondria at similar concentrations as in the cytoplasm. Thus SOD1, in addition to being a cytosolic enzyme, is present inside mitochondria in the CNS... - Nerve injection of viral vectors efficiently transfers transgenes into motor neurons and delivers RNAi therapy against ALSRui Wu
Department of Biochemistry, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
Antioxid Redox Signal 11:1523-34. 2009..These results highlight the potential and the challenges in delivering RNAi therapy by gene therapy... - RNAi therapy: dominant disease gene gets silencedZ Xu
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St-817 LRB, Worcester, MA 01655, USA
Gene Ther 12:1159-60. 2005 - Peripheral axotomy slows motoneuron degeneration in a transgenic mouse line expressing mutant SOD1 G93AJ Kong
Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA
J Comp Neurol 412:373-80. 1999..Interestingly, all of the increased surviving axons were in the axon group with diameters smaller than 4.5 microm. This result suggests an apparent threshold of vulnerability that is correlated with axon size... - Therapeutic gene silencing delivered by a chemically modified small interfering RNA against mutant SOD1 slows amyotrophic lateral sclerosis progressionHongyan Wang
Department of Biochemistry and Molecular Pharmacology, Chemical Biology Program, Cell Biology, and Neuroscience Program, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
J Biol Chem 283:15845-52. 2008..These results bring RNA interference therapy one step closer to its clinical application for treatment of chronic, devastating, and fatal CNS disorders... - Pol II-expressed shRNA knocks down Sod2 gene expression and causes phenotypes of the gene knockout in miceXu Gang Xia
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
PLoS Genet 2:e10. 2006.... - An RNAi strategy for treatment of amyotrophic lateral sclerosis caused by mutant Cu,Zn superoxide dismutaseXu Gang Xia
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts, Worcester, Massachusetts 01605, USA
J Neurochem 92:362-7. 2005..Using this strategy, all mutants and wild-type genes are inhibited by RNAi. The wild-type SOD1 function is then replaced by designed wild-type SOD1 genes that are resistant to the RNAi. Here we demonstrate the concept of this strategy... - An enhanced U6 promoter for synthesis of short hairpin RNAXu Gang Xia
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA
Nucleic Acids Res 31:e100. 2003..Thus, this enhanced U6 promoter is useful where limited choices of shRNA sequences preclude the selection of a highly efficient RNAi target region... - Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosisCheolwha Jung
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
J Neurochem 83:535-45. 2002..These results demonstrate a functional defect in mitochondria in the ventral horn region and support the view that mitochondrial damage plays a role in mutant SOD1-induced motoneuron degeneration pathway... - Inhibition of chaperone activity is a shared property of several Cu,Zn-superoxide dismutase mutants that cause amyotrophic lateral sclerosisHemachand Tummala
Department of Biochemistry and Molecular Pharmacology, Neurology, and Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
J Biol Chem 280:17725-31. 2005..Thus, mutant SOD1 proteins may impair chaperone function independent of gene expression in vivo, and this inhibition may be a shared property of ALS-linked mutant SOD1 proteins... - Multiple shRNAs expressed by an inducible pol II promoter can knock down the expression of multiple target genesXu Gang Xia
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Biotechniques 41:64-8. 2006..This method may be used to establish stable knockdown cell lines and may also prove useful for investigating gene-gene interactions in transgenic animals... - Allele-specific RNAi selectively silences mutant SOD1 and achieves significant therapeutic benefit in vivoXugang Xia
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, 817 LRB, Worcester, MA 01605, USA
Neurobiol Dis 23:578-86. 2006..The silencing of the mutant significantly delayed ALS onset and extended survival. Thus, RNAi can achieve allele-specific silencing and therapeutic benefit in vivo... - Transgenic RNAi: Accelerating and expanding reverse genetics in mammalsXu Gang Xia
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Transgenic Res 15:271-5. 2006..The advent of RNAi is poised to accelerate the pace at which reverse genetics can be applied to study gene function in mammals... - Synthetic superoxide dismutase/catalase mimetics reduce oxidative stress and prolong survival in a mouse amyotrophic lateral sclerosis modelC Jung
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655, USA
Neurosci Lett 304:157-60. 2001..These treatments reduced levels of oxidative stress and prolonged survival. The results suggest that oxidative stress plays an active role in ALS and illustrate the potential for treatment strategies aimed specifically against ROS... - Designing siRNA that distinguish between genes that differ by a single nucleotideDianne S Schwarz
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
PLoS Genet 2:e140. 2006..Our data suggest that siRNAs can be designed to discriminate between the wild-type and mutant alleles of many genes that differ by just a single nucleotide... - S-nitrosothiol depletion in amyotrophic lateral sclerosisChristopher M Schonhoff
Department of Medicine and Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA
Proc Natl Acad Sci U S A 103:2404-9. 2006..SNO donor compounds may provide new therapeutic options for diseases such as ALS that are associated with deficient S-nitrosylation... - A quantitative histochemical assay for activities of mitochondrial electron transport chain complexes in mouse spinal cord sectionsCheolwha Jung
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
J Neurosci Methods 114:165-72. 2002.... - Asymmetry in the assembly of the RNAi enzyme complexDianne S Schwarz
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Lazare Research Building, 364 Plantation Street, Worcester, MA 01605, USA
Cell 115:199-208. 2003..Thus, the common step of RISC assembly is an unexpected source of asymmetry for both siRNA function and miRNA biogenesis... - Normal dendritic arborization in spinal motoneurons requires neurofilament subunit LZaixiang Zhang
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester 01655, USA
J Comp Neurol 450:144-52. 2002..These results demonstrate that NF-L is a critical intrinsic factor for dendritic growth in large motoneurons... - Promises and challenges in developing RNAi as a research tool and therapy for neurodegenerative diseasesXu Gang Xia
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, 01605, USA
Neurodegener Dis 2:220-31. 2005..We discuss the present and future challenges in the full realization of the potential for RNAi... - Aberrantly increased hydrophobicity shared by mutants of Cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosisAshutosh Tiwari
Department of Neurology, University of Massachusetts Medical School, Worcester, 01655, USA
J Biol Chem 280:29771-9. 2005..These abnormally hydrophobic SOD1 species may promote aberrant interactions of the enzyme with itself or with other cellular constituents to produce toxicity in familial ALS... - SMN protects cells against mutant SOD1 toxicity by increasing chaperone activityTie Zou
Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB 325, Worcester, MA 01605, USA
Biochem Biophys Res Commun 364:850-5. 2007..We conclude that SMN plays a protective role in motor neurons by its chaperone activity. Our results provide support for the potential development of therapy for SMA and amyotrophic lateral sclerosis (ALS)... - Mitochondrial dysfunction and its role in motor neuron degeneration in ALSGiovanni Manfredi
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street A-501, New York, NY 10021, USA
Mitochondrion 5:77-87. 2005.... - Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in miceHongxia Zhou
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Int J Biol Sci 3:242-50. 2007..The results demonstrate that silencing of the PINK1 gene does not induce a reliable mouse model for Parkinson's disease, but that technically the inducible U6 promoter is useful for conditional RNAi in vivo... - Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS modelHitoshi Kikuchi
Department of Neurology, Columbia University, New York, NY 10032, USA
Proc Natl Acad Sci U S A 103:6025-30. 2006..Our results suggest a toxic mechanism for mutant SOD1 by which this ubiquitously expressed pathogenic protein could affect motor neuron survival and contribute to the selective motor neuronal degeneration in ALS...
Research Grants
- Reverse genetics using RNAi in non-mouse mammalsZuoshang Xu; Fiscal Year: 2007....
- Silencing mutant SOD1 in vivo for treatment of ALSZuoshang Xu; Fiscal Year: 2007..If successful, these experiments will provide impetus for further human trials of this therapeutic strategy. ..
- Modeling Progranulin hypomorphism for FTD in miceZuoshang Xu; Fiscal Year: 2007..If successful, our work will establish the first animal model for this disease, which can be used for studying neurodegeneration mechanisms and testing therapeutic strategies. ..
- Understanding mechanism and therapy of ALS using RNAiZuoshang Xu; Fiscal Year: 2007..To determine the optimal time for therapy, we will use the Tamoxifeninducible Cre recombinant system to determine at what stage of the disease induction of shRNA to suppress mutant SOD1expresion is most effective. ..
- DISEASE PROGRESSION AND OXIDATIVE STRESS IN ALSZuoshang Xu; Fiscal Year: 2002..Further, we will test whether and how anti-oxidant treatment changes the course of disease progression. ..
- Mitochondrial dysfunction in ALSZuoshang Xu; Fiscal Year: 2003..A direct association of mutant SOD1 with mitochondria will suggest that mitochondria are damaged directly by the toxicity of mutant enzyme. ..
- Developing animal models for diseases using RNAiZuoshang Xu; Fiscal Year: 2005..If successful, this technology can be widely applied as an alternative to gene knockout technology for investigation of gene functions in vivo and generation of animal disease models. ..
- Transgenic models of ALS caused by VAPB mutationZuoshang Xu; Fiscal Year: 2010..We propose to establish cell culture and transgenic mouse models to investigate how the VAPB mutation causes neuronal degeneration. Once established, these models can be used for pre-clinical tests of therapeutic compounds. ..