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

Gyeongrin Park, Namhoon Kim, Seon-Yong Kim, Hyeonjeong Lee, Cathena Meiling Li, Jae Hong Seol, Se-Young Choi and Yong-Keun Jung ()
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Gyeongrin Park: Seoul National University
Namhoon Kim: Seoul National University
Seon-Yong Kim: Seoul National University School of Dentistry
Hyeonjeong Lee: Seoul National University
Cathena Meiling Li: Seoul National University
Jae Hong Seol: Seoul National University
Se-Young Choi: Seoul National University School of Dentistry
Yong-Keun Jung: Seoul National University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65668-1

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