Brody disease is a “rare” genetic disorder due to defects in SERCA1 gene and it is characterized by exercise-induced muscle stiffness and impairment of relaxation (Brody 1996). Bovine “congenital pseudomyotonia” (PMT) is a genetic muscular disorder very similar to human Brody myopathy for clinical signs. A missense mutation in the ATP2A1 gene (Drögemüller et al 2008), encoding sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1), causes congenital PMT in cattle and Brody disease in humans. The mouse is the preferred animal model for preclinical evaluation of new therapeutic molecules. Unfortunately, it is not available for Brody disease (due to the prevalence of type II fibers in diaphragm muscle). Clinical symptoms genetic and biochemical findings clearly demonstrated that congenital PMT in Chianina cattle is the real analogue of Brody myopathy (Sacchetto et al 2009). Our findings show that a SERCA1 mutation in bovine PMT results in a protein that is most likely misfolded, ubiquitinated, and destroyed prematurely by the ubiquitin-proteasome system, albeit retaining its catalytic capabilities (Bianchini et al. 2014). The treatment with proteasome inhibitors restores SERCA levels and Ca2+ homeostasis in a cellular model and in muscle fibres from PMT affected animals (ex vivo experiments) (collected in conformance with the institutional guidelines for the care and use of animals). At present, neither specific therapy nor mouse model for Brody myopathy exists. However, a novel pharmacological approach based on the use of protein folding correctors known as CFTR (Cystic Fibrosis Transmembrane Regulator) explored in Cystic Fibrosis has recently been created and demonstrated in vitro. In a HEK293 cell model, treatment with CFTR correctors restored the expression level of mutated SERCA1. These data have been confirmed in vivo by local treatments of bovine PMT muscle with the most effective in vitro CFTR corrector. (Pharmacological treatments and biopsies were authorized by the Italian Ministry of Health-authorization ID 1251/2021.) Besides, treatments with the same CFTR corrector on SERCA1 mutated zebrafish line Accordion, are ongoing.
Brody Disease: A Novel Potential Therapeutic Approach for This Rare Human Disease
AKYUREK, EYLEM EMEK;BIANCHINI, ELISA;SANDONÀ, DORIANNA;SACCHETTO, ROBERTA.
2022
Abstract
Brody disease is a “rare” genetic disorder due to defects in SERCA1 gene and it is characterized by exercise-induced muscle stiffness and impairment of relaxation (Brody 1996). Bovine “congenital pseudomyotonia” (PMT) is a genetic muscular disorder very similar to human Brody myopathy for clinical signs. A missense mutation in the ATP2A1 gene (Drögemüller et al 2008), encoding sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1), causes congenital PMT in cattle and Brody disease in humans. The mouse is the preferred animal model for preclinical evaluation of new therapeutic molecules. Unfortunately, it is not available for Brody disease (due to the prevalence of type II fibers in diaphragm muscle). Clinical symptoms genetic and biochemical findings clearly demonstrated that congenital PMT in Chianina cattle is the real analogue of Brody myopathy (Sacchetto et al 2009). Our findings show that a SERCA1 mutation in bovine PMT results in a protein that is most likely misfolded, ubiquitinated, and destroyed prematurely by the ubiquitin-proteasome system, albeit retaining its catalytic capabilities (Bianchini et al. 2014). The treatment with proteasome inhibitors restores SERCA levels and Ca2+ homeostasis in a cellular model and in muscle fibres from PMT affected animals (ex vivo experiments) (collected in conformance with the institutional guidelines for the care and use of animals). At present, neither specific therapy nor mouse model for Brody myopathy exists. However, a novel pharmacological approach based on the use of protein folding correctors known as CFTR (Cystic Fibrosis Transmembrane Regulator) explored in Cystic Fibrosis has recently been created and demonstrated in vitro. In a HEK293 cell model, treatment with CFTR correctors restored the expression level of mutated SERCA1. These data have been confirmed in vivo by local treatments of bovine PMT muscle with the most effective in vitro CFTR corrector. (Pharmacological treatments and biopsies were authorized by the Italian Ministry of Health-authorization ID 1251/2021.) Besides, treatments with the same CFTR corrector on SERCA1 mutated zebrafish line Accordion, are ongoing.
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