About Dr. Hongxia Zhou
Devoted to reveal the causes and identify the treatments for neurodegenerative diseases including amyotrophic lateral sclerosis (ALS).
My research projects are funded by multiple NIH grants (R01NS073829 and R01NS089701). The projects are designed to study the molecular mechanisms underlying neurodegeneration in ALS and in the other neurodegenerative diseases. Using advanced genetic tools, we have created novel transgenic and knockin rats as relevant models for in vivo study on neurodegeneration.
1). Neurodegeneration in ALS is partially reversible in a rat model. Using a tetracycline-inducible gene expression system, we examined the reversibility of neurodegeneration in an ALS model. We found that neurons are prevented from demise in paralyzed rats after the ALS-causing gene TDP-43 is stopped from further expression. Motor function is partially recovered in the rats due to functional compensation from survived neurons. As no effective treatment is currently available for ALS, our finding will encourage every effort to search for therapeutic treatments for the disease.
2). Reactive astrocytes secrete neurotoxic factors such as LCN2 to promote neuron death in neurodegenerative diseases. Astrocytes often become reactive in neurodegenerative diseases and reactive astrocytes are believed to be harmful to neurons. How reactive astrocytes exert a toxicity on neurons is not clear. We used comprehensive approach in search of potent molecules mediating astrocytic neurotoxicity. We identified that reactive astrocytes secrete lipocalin 2 (LCN2) as a potent mediator of astrocytic neurotoxicity. LCN2 is known to stimulate quiescent astrocytes and microglia to become reactive. Caution must be taken when glial replacement is tested for therapeutic effects against neurological diseases.
3). Multiple lines of mutant rats are created for studying the mechanisms of neurodegeneration. We have created many mutant rats which express human disease genes and develop disease-reminiscent phenotypes. We have deposited these novel rats to RRRC rat resource and research center (www.rrrc.us) for free distribution to academic investigators.
Along with my long-term collaborator Dr. Xugang Xia, I am leading my research team to reveal disease mechanisms and identify effective treatment for neurodegenerative diseases.
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 (corresponding author), Xia XG. Pathogenic Ubqln2 gains toxic properties to induce neuron death. Acta Neuropathol 2015, 129 (3): 417-428
Huang C, Huang B, Bi F, Yan LH, Tong J, Huang J, Xia XG, Zhou H. Profiling the genes affected by pathogenic TDP-43 in astrocytes. J Neurochem 2014; 129 (6):932-9.
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 (corresponding author), 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 (corresponding author), 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.
Tong J, Huang C, Bi F, Wu Q, Huang B, Zhou H. XBP1 depletion precedes ubiquitin aggregation and Golgi fragmentation in TDP-43 transgenic rats. Journal of Neurochemistry 2012, 123 (3): 406-416.
Huang C, Tong J, Bi F, Wu Q, Huang B, Zhou H (corresponding author), 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 (corresponding author), 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 (corresponding author), 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 (corresponding author), 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 (corresponding author), and Xia XG. TDP-43 potentiates α-synuclein toxicity to dopaminergic neurons in transgenic mice. Int J Biol Sci 2011, 7: 234-243.
Huang C, Xia PY, Zhou H. Sustained expression of TDP-43 and FUS in motor neurons in rodent’s lifetime, Int J Biol Sci 2010, 4: 396-406
Zhou H (Corresponding author), 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, Yang M, Landel CP, Xia PY, Liu YJ, and Xia XG. Developing tTA transgenic rats for inducible and reversible gene expression. Int J Biol Sci 2009, 2: 171-181
Wu R, Wang H, Xia XG, Zhou H, Liu C, Castro MG, and Xu Z. Nerve injection of viral vectors efficiently transfers transgenes into motor neurons and delivers RNAi therapy against ALS. Antioxid Redox Signal 2009, 11: 1523-1534
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
Wang H, Ghosh A, Baigude H, Yang CS, Qiu L, Xia X, Zhou H, Rana TM, and 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, 283: 15845-15852
Qiu L, Wang H, Xia X, Zhou H, and Xu Z. A construct with fluorescent indicators for conditional expression of mirna, BMC Biotechnol 2008, 8:77
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 (co-first author), 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.
Trendelenburg AU, Gomeza J, Klebroff W, Zhou H, Wess J. Heterogeneity of presynaptic muscarinic receptors mediating inhibition of sympathetic transmitter release: a study with M2- and M4-receptor-deficient mice. Br J Pharmacol 2003; 138: 469-480.
Zhou H, Meyer A, Starke K, Trendelenburg AU. Heterogeneity of release-inhibiting muscarinic autoreceptors in heart atria and urinary bladder: a study with M2– and M4-receptor-deficient mice. Naunyn-Schmiedeberg’s Arch Pharmacol 2002; 365:112-122.