Key result
The CASQ2 R33Q mutation in mice led to a decrease in mutated CASQ2 soon after birth, likely due to activation of the unfolded protein response and subsequent proteasome degradation.
The R33Q mutation in CASQ2 leads to its reduction in skeletal muscle soon after birth, likely driven by unfolded protein response activation and proteasomal degradation.
Isoform 2 of calsequestrin (CASQ2) is the main calcium-binding protein of sarcoplasmic reticulum (SR), expressed both in cardiac and in skeletal muscles. CASQ2 acts as an SR calcium (Ca2+) sensor and regulates SR Ca2+ release via interactions with triadin, junctin, and the ryanodine receptor. Various mutations of the csq2 gene lead to altered Ca2+ release and contractile dysfunction contributing to the development of arrhythmias and sudden cardiac death in young individuals affected by catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, a transgenic mouse carrying one of the identified CASQ2 point-mutations (R33Q) associated to CPVT was developed and a drastic reduction of the mutated protein was observed. Following a biomolecular approach, several analysis were performed using different antibody treatments in order to identify when the reduction of CASQ2 begins in skeletal muscles, unveil the mechanism involved in the reduction of CASQ2 in slow-twitch and fast twitch muscles and verify if other proteins are affected by the presence of the mutated protein. Mutated CASQ2 decreased soon after birth. Up-regulation of proteins associated to the unfolded protein response (UPR) was also observed. Important proteins in skeletal muscle triads formation were analyzed and increased protein levels were observed in adult knock-in CASQ2-R33Q/R33Q mice. Probably, R33Q mutation induced the decrease of CASQ2 by activation of the UPR and subsequently degradation through proteasome.
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Rigers Bakiu (2013) studied Catecholaminergic polymorphic ventricular tachycardia (CPVT). CASQ2 R33Q mutation was evaluated on CASQ2 protein levels and unfolded protein response (UPR). The CASQ2 R33Q mutation in mice led to a decrease in mutated CASQ2 soon after birth, likely due to activation of the unfolded protein response and subsequent proteasome degradation.
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