MODERATE ACCUMULATION OF TDP-43 IN NEURONS IS SUFFICIENT TO CAUSE ADULT-ONSET MOTOR NEURON DISEASE

Amyotrophic Lateral Sclerosis;TAR DNA Binding Protein;TDP-43;Transgenic Mouse Model;not listed

Tsao, William Wei-LiangMankowski, Joseph L. ;

Johns Hopkins University

关键词: Amyotrophic Lateral Sclerosis;    TAR DNA Binding Protein;    TDP-43;    Transgenic Mouse Model;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/40680/TSAO-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), accompanied by its nuclear clearance, is a key common pathological hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD).Mutations in TARDBP (the gene encoding TDP-43) linked to familial and sporadic ALS established this essential RNA binding protein to play a central role in the pathogenesis of ALS and FTLD.While most mutations cluster within the C-terminal, prion-like domain of TDP-43, a few are found within the 3’ untranslated region (3’ UTR) where TDP-43 binds and regulates the level of its own mRNA.ALS cases harboring the 3’ UTR mutation exhibited modest elevation of TDP-43, possibly because the mutation compromised the ability of TDP-43 to downregulate its own transcript.To determine whether modest increase of TDP-43 is sufficient to cause motor neuron disease, two lines of transgenic mice that accumulate modest levels of TDP-43 in the nervous system are generated and characterized.One of these lines, S97, expressed TARDBP carrying the ALS associated missense mutation (corresponding to the mutant G298S protein), whereas the other line, W2, expressed wild-type human TARDBP.S97 and W2 transgenic mice survive to adulthood, gain weight appropriately before plateauing, exhibit a progressive loss of strength, and lose large motor axons in their adult life.Also, S97 and W2 transgenic mice display adult-onset muscle degeneration and neuromuscular junction and motor end-plate abnormalities.Significantly, a percentage of S97 and W2 transgenic mice progress to paralysis late in life.The S97 and W2 lines represent the first transgenic TDP-43 lines with mice that exhibit motor neuron degeneration leading to paralysis in late adulthood.As such, these mouse lines will be useful to further clarify disease mechanisms and for testing therapeutic strategies to attenuate neurodegeneration in ALS.Advisor: Dr. Philip C. WongReaders: Dr. Philip C. Wong and Dr. Joseph L. Mankowski