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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Gubitz, Amelie
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Thomas Jefferson University
Schools of Medicine
United States
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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; 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
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
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