Tardbp-flox Mouse

Tardbp, encoding the transactive response DNA binding protein of 43 kDa (TDP-43), is an intranuclear protein involved in RNA splicing, trafficking, and stabilization, thus regulating gene expression [2]. It also plays a role in alternative splicing regulation, for example, in ovarian cancer, Tardbp can regulate the alternative splicing of vascular endothelial growth factor (VEGF) via serine/arginine-rich splicing factor 1 (SRSF1), promoting ovarian cancer angiogenesis [3].

Mutations in Tardbp are associated with multiple neurodegenerative diseases. In Chinese patients with amyotrophic lateral sclerosis (ALS), the mutant frequency of Tardbp variants was 0.3% in a single-center study, and when combined with literature data, 1.4% in the Chinese population, with 7.0% in familial ALS (fALS) [1]. Different Tardbp mutations were associated with specific phenotypic features, such as different disease durations [1]. Also, Tardbp mutations have been found in semantic variant primary progressive aphasia (svPPA) associated with motor neuron disease (MND) [4], and a novel Tardbp missense mutation caused familial ALS with frontotemporal dementia and parkinsonism [5]. TDP-43 cytoplasmic inclusion bodies are a hallmark of ALS and a subset of frontotemporal lobar degeneration (FTLD), and TDP-43 inclusions are also found in Alzheimer's disease (AD), with AD patients having increased cognitive impairment when TDP-43 pathology is present [2].

In conclusion, Tardbp is crucial for RNA-related functions. Its mutations are significantly associated with neurodegenerative diseases like ALS, FTLD, and AD, as well as ovarian cancer. Understanding Tardbp's functions through research on its mutations helps in uncovering the pathogenesis of these diseases, providing potential directions for diagnosis and treatment.