Understanding the Mechanisms of TDP-43 Function

Project: Research project

Description

DESCRIPTION (provided by applicant): 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. .
StatusFinished
Effective start/end date2/15/131/31/16

Funding

  • National Institutes of Health: $232,403.00
  • National Institutes of Health: $195,625.00

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Tyrosine
Phosphorylation
Frontotemporal Dementia
Bacterial Artificial Chromosomes
Amyotrophic Lateral Sclerosis
Ubiquitin
Transgenic Mice

ASJC

  • Medicine(all)
  • Neuroscience(all)