Vapb, also known as Vesicle-associated membrane protein-associated protein B, is an ER-anchored protein. It plays a crucial role in mediating tethers between the endoplasmic reticulum (ER) and membranes of other organelles, especially in forming and stabilizing mitochondria-associated endoplasmic reticulum membranes (MAMs) through interaction with PTPIP51. This interaction is vital for intracellular signaling, regulating processes like calcium homeostasis, lipid metabolism, mitochondrial function, and apoptosis [1,4]. It is also involved in insulin/IGF signaling by stabilizing IRS-1 signalosomes through ER-targeting [2].

In a mouse model of cerebral ischemia-reperfusion injury (CIRI), knockdown of VapB exacerbated damage to MAMs, accompanied by excessive autophagy activation, increased reactive oxygen species (ROS) production, an enlarged infarct area, and exacerbated neurological deficits. This was associated with the inhibition of the PI3K/AKT/mTOR pathway [4]. In medulloblastoma cells, knockout of VapB (VapBKO) delayed cell cycle progression and decreased the transcript levels of WNT-related proteins, indicating its requirement for normal proliferation rates [5]. In ALS, the mutant VapB (P56S) is aggregation-prone, non-functional, and unstable, and VapB haploinsufficiency may be the main driver of the disease, with studies on VapB deficit in cellular and animal models showing effects on basic cell physiological processes [3,6].

In conclusion, VapB is essential for maintaining MAMs, regulating insulin/IGF signaling, and influencing cell proliferation. Studies using gene knockout mouse models in diseases such as ischemic stroke, medulloblastoma, and ALS have revealed its role in disease-related processes, highlighting its potential as a therapeutic target in these conditions.