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TUSC3 regulates ERMA-mediated Mg2+ uptake for synaptic function and neurodevelopment

Gyeongrin Park,Namhoon Kim,Seon-Yong Kim,Hyeonjeong Lee,Cathena Meiling Li,J. Seol,Se-Young Choi,Yong-Keun Jung

Published 2025 in Nature Communications

ABSTRACT

Intellectual disability (ID) is characterized by deficits in cognition and adaptive behavior, with few treatment options. Tumor Suppressor Candidate 3 (TUSC3) has been genetically linked to autosomal recessive ID, but its molecular mechanism and therapeutic potential remain unclear. Here we show that TUSC3 is essential for endoplasmic reticulum (ER) Mg²⁺ homeostasis and neuronal function. Using a TUSC3 knockout (KO) mouse model, we find ID-like phenotypes including impairments in learning, memory, stress adaptation, and social behavior. Mechanistically, TUSC3 forms an ER-localized Mg²⁺ transport complex with ERMA and its loss leads to ER Mg²⁺ depletion, PERK–eIF2α pathway activation, synaptic dysfunction, and neuronal vulnerability. Fibroblasts from TUSC3 mutant patients similarly exhibit ER Mg²⁺ deficiency and heightened ER stress. Magnesium supplementation restores ER Mg²⁺ levels, reduces ER stress, and rescues cognitive deficits. Our findings establish ER Mg²⁺ dysregulation as a key driver of neurodevelopmental dysfunction and a promising therapeutic target. This study shows that TUSC3 is essential for magnesium balance in the brain. Loss of TUSC3 disrupts neuron function and leads to intellectual disability in a mouse model, but magnesium supplementation restores brain function, pointing to a potential therapy.

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