TDP-43 is the principal component of ubiquitin-positive inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). Recently, we discovered that TDP-43 is hyper-phosphorylated at tyrosine-4 in disease and pseudo-phosphorylation of tyrosine-4 (TDP- 43Y4D) impairs TDP-43 biological activities. Therefore, our data provide a direct link between TDP-43 phosphorylation and loss of TDP-43 function, which is believed to mediate toxicity and neurodegeneration. We hypothesize that hyper-phosphorylation of TDP-43 at tyrosine-4 contributes to disease pathogenesis by reducing TDP-43 biological activities. Specifically, we will use a combination of in vitro and in vivo models to 1) investigate pathological significance o TDP-43 phosphorylation at tyrosine-4 in disease pathogenesis;2) investigate the potential mechanisms through which phosphorylation at tyrosine-4 impair TDP-43 biological activities;3) generate novel bacterial artificial chromosome (BAC) transgenic mouse model expressing human TDP-43Y4D to investigate whether TDP-43Y4D result in loss-of function in vivo. Successful completion of our novel study will undoubtedly enhance the scientific community's understanding of the TDP-43 N-terminus'role, particularly of its N-terminal phosphorylation at tyrosine-4, in disease pathogenesis, might also provide therapeutic approaches. .
Abnormally phosphorylated TDP-43 is the principal component of inclusions, or protein clumps in brain cells, associated with neurodegenerative diseases such as frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis (ALS or Lou Gehrig's), yet how it causes neurodegeneration remains unclear. The goals of this project are to 1) investigate the pathological and biological significance of TDP-43 phosphorylation at its N-terminal tyrosine-4 site;and 2) generate a novel BAC transgenic mouse model expressing TDP-43Y4D to determine whether phosphorylation of tyrosine-4 result in loss-of function in vivo. The discoveries emerging from our studies will provide insight on how TDP-43 phosphorylation and loss of TDP-43 function contribute to disease, and may lead to the identification of novel therapeutic targets for the treatment of FTLD-TDP and ALS.
|Kramer, Nicholas J; Carlomagno, Yari; Zhang, Yong-Jie et al. (2016) Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. Science 353:708-12|
|Zhang, Yong-Jie; Gendron, Tania F; Grima, Jonathan C et al. (2016) C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat Neurosci 19:668-77|
|Sasaguri, Hiroki; Chew, Jeannie; Xu, Ya-Fei et al. (2016) The extreme N-terminus of TDP-43 mediates the cytoplasmic aggregation of TDP-43 and associated toxicity in vivo. Brain Res 1647:57-64|
|Chew, Jeannie; Gendron, Tania F; Prudencio, Mercedes et al. (2015) Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348:1151-4|
|Zhang, Yong-Jie; Jansen-West, Karen; Xu, Ya-Fei et al. (2014) Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol 128:505-24|
|Cook, Casey; Dunmore, Judy H; Murray, Melissa E et al. (2014) Severe amygdala dysfunction in a MAPT transgenic mouse model of frontotemporal dementia. Neurobiol Aging 35:1769-77|
|Su, Zhaoming; Zhang, Yongjie; Gendron, Tania F et al. (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83:1043-50|
|Carlomagno, Yari; Zhang, Yongjie; Davis, Mary et al. (2014) Casein kinase II induced polymerization of soluble TDP-43 into filaments is inhibited by heat shock proteins. PLoS One 9:e90452|
|Gendron, Tania F; Belzil, Veronique V; Zhang, Yong-Jie et al. (2014) Mechanisms of toxicity in C9FTLD/ALS. Acta Neuropathol 127:359-76|
|Xu, Ya-Fei; Prudencio, Mercedes; Hubbard, Jaime M et al. (2013) The pathological phenotypes of human TDP-43 transgenic mouse models are independent of downregulation of mouse Tdp-43. PLoS One 8:e69864|
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