DEPDC5, or Dishevelled, Egl-10 and Pleckstrin domain-containing protein 5, is a protein subunit of the GTPase-activating proteins towards Rags 1 (GATOR1) complex. GATOR1 modulates the activity of the mechanistic target of rapamycin (mTOR), a key regulator of cell proliferation and metabolism. Thus, DEPDC5 is involved in the mTOR pathway, which is crucial for normal cellular function, and its disruption is implicated in various diseases [4].

In epilepsy, DEPDC5-related epilepsy is caused by pathogenic germline variants of the DEPDC5 gene. It includes familial epilepsy syndromes like familial focal epilepsy with variable foci. Null variants in DEPDC5 are related to unfavorable prognosis such as drug-resistance or sudden unexpected death in epilepsy. In mouse models, Depdc5 neuronal-specific knockout mice are resistant to the protective effects of fasting on seizures, indicating that acute fasting reduces seizure susceptibility in a DEPDC5-dependent manner. Also, T cell-specific Depdc5 deletion in mice leads to reduced peripheral CD8+ T cells and impaired anti-tumor immunity due to hyper-mTORC1-induced ferroptosis [1,2,3,5].

In conclusion, DEPDC5 plays a vital role in regulating the mTOR pathway. Studies using gene knockout mouse models have revealed its significance in epilepsy, especially in seizure susceptibility and in the context of fasting-induced anti-seizure effects. Additionally, it is involved in maintaining peripheral CD8+ T cell homeostasis and anti-tumor immunity. Understanding DEPDC5 provides insights into the mechanisms of these disease-related processes and potential therapeutic strategies.