Key result
The CSQ2-R33Q mutation in mice led to a drastic reduction in CSQ2 protein levels to 20% of wild-type levels by 8 weeks, accompanied by decreased triadin levels and activation of the unfolded protein response.
The unfolded protein response, specifically the ATF6-dependent pathway, is activated in CPVT mice with the CSQ2 R33Q mutation, coinciding with decreased levels of mutated CSQ2 and triadin.
Isoform 2 of calsequestrin (CSQ2) is the main calciumbinding protein of the sarcoplasmic reticulum (SR) and is expressed in both cardiac and skeletal muscle. CSQ2 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 and contribute to the development of arrhythmias and sudden cardiac death in young individuals affected by CPVT . Transgenic mice carrying one of the identified CSQ2 point mutations (R33Q) associated with CPVT were developed, and a drastic reduction in the mutated protein was observed. Following a biomolecular approach, several analyses were performed using different antibody treatments to identify when the reduction of CSQ2 begins, to unveil the mechanism involved in the reduction of CSQ2 and to verify whether other proteins are affected by the presence of the mutated protein. Th e results of this study showed that mutated CSQ2 levels decreased soon after birth, in conjunction with decreased levels of other important junctional SR proteins, including triadin (TD). Th e up-regulation of proteins associated with the unfolded protein response (UPR) was also observed, and the ATF6- dependent pathway was
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Rigers Bakiu (2014) studied Catecholaminergic polymorphic ventricular tachycardia (CPVT) (n=8). CSQ2-R33Q mutation vs. Wild-type (wt/wt) mice was evaluated on CSQ2 protein levels at 8 weeks (p=<0.05). The CSQ2-R33Q mutation in mice led to a drastic reduction in CSQ2 protein levels to 20% of wild-type levels by 8 weeks, accompanied by decreased triadin levels and activation of the unfolded protein response.
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