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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.

One or more keywords matched the following items that are connected to Xu, Zuoshang
Item TypeName
Academic Article Mechanism and treatment of motoneuron degeneration in ALS: what have SOD1 mutants told us?
Academic Article ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes.
Academic Article Aberrantly increased hydrophobicity shared by mutants of Cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosis.
Academic Article Allele-specific RNAi selectively silences mutant SOD1 and achieves significant therapeutic benefit in vivo.
Academic Article Therapeutic gene silencing delivered by a chemically modified small interfering RNA against mutant SOD1 slows amyotrophic lateral sclerosis progression.
Academic Article A quantitative histochemical assay for activities of mitochondrial electron transport chain complexes in mouse spinal cord sections.
Academic Article Mutant Cu, Zn superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNS.
Academic Article Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis.
Academic Article Mitochondrial degeneration in amyotrophic lateral sclerosis.
Academic Article An RNAi strategy for treatment of amyotrophic lateral sclerosis caused by mutant Cu,Zn superoxide dismutase.
Academic Article Inhibition of chaperone activity is a shared property of several Cu,Zn-superoxide dismutase mutants that cause amyotrophic lateral sclerosis.
Academic Article S-nitrosothiol depletion in amyotrophic lateral sclerosis.
Academic Article Nerve injection of viral vectors efficiently transfers transgenes into motor neurons and delivers RNAi therapy against ALS.
Academic Article Does a loss of TDP-43 function cause neurodegeneration?
Academic Article Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis.
Academic Article Widespread aggregation of mutant VAPB associated with ALS does not cause motor neuron degeneration or modulate mutant SOD1 aggregation and toxicity in mice.
Academic Article Identification of human monoclonal antibodies specific for human SOD1 recognizing distinct epitopes and forms of SOD1.
Concept Motor Neuron Disease
Concept Amyotrophic Lateral Sclerosis
Academic Article Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis.
Academic Article TDP-43-The key to understanding amyotrophic lateral sclerosis.
Academic Article Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity.
Academic Article Imaging Net Retrograde Axonal Transport In Vivo: A Physiological Biomarker.
Academic Article Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons.
Academic Article Protein citrullination marks myelin protein aggregation and disease progression in mouse ALS models.
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  • Motor Neuron Disease