Amyotrophic lateral sclerosis (ALS) results from progressive degeneration of motor neurons. ALS inexorably progresses to paralysis and to death within an average of 5 years. Of the few treatments, none substantially prolongs life or improves the quality of life. A major hurdle to developing effective therapy for ALS is a limited understanding of the disease mechanisms. A recent advance in ALS research comes with the discovery of TDP- 43 proteinopathy and TDP mutation. When overexpressed in transgenic rodents, mutant TDP-43 causes progressive neurodegeneration accompanied by severe glial reaction. To dissect the mechanisms underlying neurodegeneration caused by TDP mutation, we have developed transgenic rats reversibly expressing mutant TDP-43 in neurons or in astrocytes. By microarray analysis, we also have identified candidate genes responsive to glial reaction in mutant TDP-43 transgenic rats. Using TDP-43 transgenic rats (in vivo model) and primary cell cultures (in vitro model) as complementary models, we will resolve the following critical questions regarding TDP-43 pathogenesis: 1) how glial reaction correlates with the neurodegeneration caused by TDP mutation;2) whether presence of mutant TDP-43 in astrocytes accelerates glial activation;3) what molecules mediate the propagation of glial reaction in response to TDP mutation;4) how astrocytes expressing mutant TDP-43 produce neurotoxicity;5) how expression of mutant TDP-43 in astrocytes affects onset and progression of ALS in transgenic rats;and 6) whether continuous presence of mutant TDP-43 is required for disease progression. Proposed studies will not only develop desirable animal models for ALS research, but also would establish a foundation for developing ALS therapies targeting astrocytes or mutant TDP-43.
Using transgenic rats and primary cells as complementary models, this proposal will dissect the mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis and will provide a foundation for developing ALS therapies.
|Huang, Bo; Wu, Qinxue; Zhou, Hongxia et al. (2016) Increased Ubqln2 expression causes neuron death in transgenic rats. J Neurochem 139:285-293|
|Wu, Qinxue; Liu, Mujun; Huang, Cao et al. (2015) Pathogenic Ubqln2 gains toxic properties to induce neuron death. Acta Neuropathol 129:417-28|
|Huang, Cao; Huang, Bo; Bi, Fangfang et al. (2014) Profiling the genes affected by pathogenic TDP-43 in astrocytes. J Neurochem 129:932-9|
|Bi, Fangfang; Li, Fang; Huang, Cao et al. (2013) Pathogenic mutation in VPS35 impairs its protection against MPP(+) cytotoxicity. Int J Biol Sci 9:149-55|
|Bi, Fangfang; Huang, Cao; Tong, Jianbin et al. (2013) Reactive astrocytes secrete lcn2 to promote neuron death. Proc Natl Acad Sci U S A 110:4069-74|
|Tong, Jianbin; Huang, Cao; Bi, Fangfang et al. (2013) Expression of ALS-linked TDP-43 mutant in astrocytes causes non-cell-autonomous motor neuron death in rats. EMBO J 32:1917-26|
|Huang, Cao; Tong, Jianbin; Bi, Fangfang et al. (2012) Entorhinal cortical neurons are the primary targets of FUS mislocalization and ubiquitin aggregation in FUS transgenic rats. Hum Mol Genet 21:4602-14|
|Tong, Jianbin; Huang, Cao; Bi, Fangfang et al. (2012) XBP1 depletion precedes ubiquitin aggregation and Golgi fragmentation in TDP-43 transgenic rats. J Neurochem 123:406-16|
|Huang, Cao; Tong, Jianbin; Bi, Fangfang et al. (2012) Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats. J Clin Invest 122:107-18|