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.
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