About Dr. Xugang Xia
Searching for genetic mutations causing neurodegenerative diseases and revealing molecular mechanisms underlying neurodegeneration in the diseases
Initially trained as a neurologist and further trained as a researcher, I have a passion for understanding and treating neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To examine disease mechanisms, we choose the rats rather than the mice as a relevant animal model to reproduce disease phenotypes observed in patients carrying a genetic mutation and we use multidisciplinary approach to reveal molecular pathways leading to neurodegeneration in disease conditions.
The laboratory rats are chosen to express causative genetic mutations at physiological or excessive levels. Compared to laboratory mice, laboratory rats are easier for behavioral tests and for multiple samplings and thus are chosen for expressing disease-causing mutations. Our team has established a system for producing transgenic, knockin, and knockout rats by pronuclear injection of transgene DNA and CRISPR/Cas9 encoded RNA. We have created many lines of mutant rats and have deposited characterized rat lines to the RRRC rat resource and research center (www.rrrc.us) for free distribution to academic investigators.
Disease mechanisms are examined in mutant rats for ALS. We reproduce disease phenotypes in transgenic or knockin rats expressing a disease-causing mutation and examine the effects of pathogenic mutation on gene function at a systematic level. We have unequivocally shown that overexpression of the ALS gene TPD-43 in the motor neurons or the astrocytes is sufficient to cause cell-autonomous or non-cell-autonomous neurodegeneration in a rat model. We found that motor function is partially reversible in a rat model for the ALS. Using RNA sequencing and proteomics, we are going to reveal molecular mechanisms underlying neuronal death in the disease. Meanwhile, our team is searching for genetic mutation causing a recessive form of familial ALS.
Genetic causes are investigated for familial PD. We are collaborating with researchers worldwide to discover novel genes in which pathogenic mutations cause PD in affected families. Using mutant rats as a relevant model, we are going to examine candidate genes for the effect of a mutation on dopaminergic function at a systematic level.
Huang B, Wu Q, Zhou H, Huang C, and Xia XG. Increased Ubqln2 expression causes neuron death in transgenic rats. J Neurochem 2016;139 (2):285-293.
Wu Q, Liu M, Huang C, Liu X, Huang B, Li N, Zhou H, Xia XG. Pathogenic Ubqln2 gains toxic properties to induce neuron death. Acta Neuropathol 2015, 129 (3): 417-428
Bi F, Huang C, Tong J, Qiu G, Huang B, Wu Q, Li F, Xu Z, Bowser R, Xia XG, and Zhou H. Reactive Astrocytes Secrete LCN2 to Promote Neuron Death. Proc. Natl. Acad. Sci. U.S.A. 2013; 110 (10): 4069-4074
Tong J, Huang C, Bi F, Wu Q, Huang B, Liu X, Li F, Zhou H, Xia XG. Expression of ALS-linked TDP-43 mutant in astrocytes causes non-cell-autonomous motor neuron death in rats. EMBO J 2013; 32 (13): 1917-1926
Huang C, Tong J, Bi F, Zhou H, Xia XG. Mutant TDP-43 in Motor Neurons Promotes the Onset and Progression of ALS in Rats. The Journal of Clinical Investigation 2012, 122 (1): 107-118.
Huang C, Tong J, Bi F, Wu Q, Huang B, Zhou H, Xia XG. Entorhinal cortical neurons are the primary targets of FUS mislocalization and ubiquitin aggregation in FUS transgenic rats. Human Molecular Genetics 2012, 21 (21): 4602-4614.
Huang C, Zhou H, Tong J, Chen H, Wang D, Wei X, and Xia XG. FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration. PLoS Genet 2011, 7(3): e1002011.
Zhou H, Huang C, Tong JB, and Xia XG. Early Exposure to Paraquat Sensitizes Dopaminergic Neurons to Subsequent Silencing of PINK1 Gene Expression in Mice. Int J Biol Sci 2011, 7 (8): 1180-1187.
Zhou H, Huang C, Tong J, Hong WC, Liu YJ, and Xia XG. Temporal Expression of Mutant LRRK2 in Adult Rats Impairs Dopamine Reuptake. Int J Biol Sci 2011, 7 (6): 753-761.
Tian T, Huang C, Yang M, Tong J, Zhou H, and Xia XG. TDP-43 potentiates α-synuclein toxicity to dopaminergic neurons in transgenic mice. Int J Biol Sci 2011, 7: 234-243.
Zhou H, Huang C, Chen H, Wang D, Landel C, Xia PY, Bowser R, Liu YJ, Xia XG. Transgenic Rat Model of Neurodegeneration Caused by Mutation in the TDP Gene, PLOS Genetics 2010, Mar 26;6(3): e1000887
Zhou H, Huang C, and Xia XG. A tightly regulated pol III promoter for synthesis of miRNA genes in tandem, Biochim Biophys Acta 2008, 1779: 773-779
Zhou H, Falkenburger BH, Schulz JB, Tieu K, Xu Z, and Xia XG. Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in mice. Int J Biol Sci 2007, 3(4): 242-50.
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; 2(1): e10.
Xia XG, Zhou H, Huang Y, Xu Z. Allele-specific RNAi Selectively Silences Mutant SOD1 and Achieves Significant Therapeutic Benefit in vivo. Neurobiol Dis 2006; 23(3): 578-86.
Zhou H, Xia XG, Xu Z. An optimized RNA polymerase II construct for synthesis of short hairpin RNA and gene silencing. Nucleic Acids Research 2005; 33(6): e62.
Xia XG, Zhou H, Zhou S, Yu Y, Xu Z. An RNAi strategy for treatment of amyotrophic lateral sclerosis caused by mutant Cu,Zn superoxide dismutase. J Neurochem 2005; 92: 362–367.
Xia XG, Harding T, Weller M, Bieneman A, Uney JB and Schulz JB. Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci USA 2001, 98: 10433-8.
Xia XG, Schmidt N, Teismann P, Ferger B and Schulz JB. Reconstitution of striatal malonate toxicity in 6-OHDA lesioned animals by dopamine and D2 but not by D1 agonists. J Neurochem 2001, 279: 63-70.