{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nVAPB is an integral endoplasmic reticulum (ER)–resident protein that orchestrates multiple aspects of intracellular organization. Through its highly conserved N‐terminal major sperm protein (MSP) domain and its ability to bind FFAT‐motif–containing partners, VAPB establishes membrane contact sites that tether the ER to diverse organelles. These include mitochondria via interactions with the outer mitochondrial membrane protein PTPIP51, peroxisomes through binding to ACBD5, and the Golgi apparatus by engaging lipid transfer proteins such as OSBP and CERT. In addition, VAPB participates in regulating ER structure and dynamics – for example, by modulating tubular ER remodeling and even serving as a secreted ligand for Eph receptors – while also forming part of novel tethering complexes with proteins like MOSPD2 and functioning in ER‐phagy through association with receptors such as CALCOCO1. Such multifaceted roles are further supported by studies revealing its involvement in lipid exchange, cholesterol trafficking, and maintenance of proteostasis via interactions that influence lateral membrane diffusion and vesicle formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its structural roles, VAPB is critical for the regulation of intracellular Ca²⁺ dynamics and mitochondrial function. By tethering ER to mitochondria via its interaction with PTPIP51, VAPB facilitates efficient Ca²⁺ transfer from ER stores to mitochondria—a process essential for maintaining optimal mitochondrial ATP production and overall cellular energy homeostasis. Disruption of these ER–mitochondria contacts, whether through altered expression or via pathogenic mutations (for example, P56S or T46I), compromises Ca²⁺ signaling, impairs mitochondrial transport in neurons, and perturbs the unfolded protein response (UPR), thereby linking VAPB dysfunction to cellular stress responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_fs", "start_ref": "15", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in the VAPB gene are genetically linked to familial motor neuron diseases, including the autosomal dominant ALS8. Both toxic gain-of-function mechanisms—exemplified by protein aggregation and aberrant inclusion formation—and loss-of-function outcomes that reduce normal VAPB levels have been observed in patient-derived cells and animal models. These alterations perturb ER integrity, vesicle trafficking, and proteostasis, and are associated with defects in synaptic architecture, nuclear envelope assembly, and activation of pro-apoptotic pathways. Indeed, reduced VAPB expression correlates with motor neuron degeneration in both familial and sporadic ALS cases, emphasizing its critical role in neuronal homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kurt J De Vos, Gábor M Mórotz, Radu Stoica, et al. 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