huTARDBP-Q331K/M337V/A382T Mouse

TAR DNA-binding protein 43 (TARDBP/TDP43) is a crucial protein involved in RNA processing, transport, and metabolism. Its aggregation in the cytoplasm is a key pathological feature of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). TDP43 is a multifunctional nuclear protein and is the main component of ubiquitin-positive cytoplasmic inclusions found in residual motor neurons of sporadic and familial ALS, with cytoplasmic TDP43 inclusions observed in almost all ALS cases ^[1]. TDP43 is typically localized in the cell nucleus but can shuttle between the nucleus and cytoplasm to perform various functions, including regulating RNA splicing, transport, and homeostasis. Both cytoplasmic mislocalization and nuclear loss of TDP43 are associated with ALS and FTD, and the proper function of TDP43 is ensured by strictly controlled nucleocytoplasmic transport, which regulates its expression levels and correct cellular localization ^[2].

The synergy of the Q331K, M337V, and A382T mutations within the C-terminal glycine-rich domain of TARDBP creates a potent driver of neurodegeneration by fundamentally altering the protein's biophysical properties and cellular localization ^[3]. Individually, Q331K promotes the formation of toxic C-terminal fragments and disrupts RNA splicing, while M337V accelerates the kinetics of irreversible fibrillization and impairs mitochondrial transport ^[4]. A382T further exacerbates this pathology by promoting nucleocytoplasmic mislocalization and inducing R-loop-mediated DNA damage ^[5]. When combined in a humanized model, these mutations act in concert to trigger robust TDP-43 proteinopathy, characterized by the loss of essential nuclear regulatory functions and the gain of cytoplasmic aggregate toxicity. This pathological cascade directly mirrors the clinical progression of ALS and FTD, leading to selective motor neuron loss, cognitive decline, and the formation of phosphorylated inclusions that are hallmarks of the ALS-FTD spectrum.

huTARDBP-Q331K/M337V/A382T was generated by introducing the p.Q331K (CAG to AAG), p.M337V (ATG to GTG), and p.A382T (GCA to ACA) point mutations into exon 6 of the human TARDBP gene in huTARDBP mice (Catalog Number: C001418). This model serves as a valuable tool for studying neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), and can be used to investigate the effects of TDP‑43 protein aggregation in related disorders.