Understanding the Mechanisms of TDP-43 Function

描述(申请人提供)：TDP-43是泛素阳性包涵体在额颞叶变性伴泛素阳性包涵体(FTLD-TDP)和肌萎缩侧索硬化(ALS)中的主要成分。最近，我们发现在疾病中TDP-43在酪氨酸-4处被过度磷酸化，而酪氨酸-4(TDP-43Y4D)的伪磷酸化削弱了TDP-43的生物学活性。因此，我们的数据提供了TDP-43磷酸化和TDP-43功能丧失之间的直接联系，这被认为是介导毒性和神经退行性变的原因。我们假设TDP-43在酪氨酸-4处的过度磷酸化通过降低TDP-43的生物活性而参与疾病的发病。具体地说，我们将利用体外和体内模型相结合的方法1)探讨TDP-43酪氨酸-4的磷酸化在疾病发病机制中的病理学意义；2)研究TDP-4酪氨酸磷酸化损害TDP-43生物活性的潜在机制；3)建立新型细菌人工染色体(BAC)转基因表达人TDP-43Y4D的小鼠模型，以研究TDP-43Y4D在体内是否会导致功能丧失。我们新研究的成功完成无疑将加强科学界对TDP-43N末端的作用的理解，特别是它在疾病发病机制中的N末端酪氨酸4的磷酸化，也可能提供治疗方法。。

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. .