Molecular mechanisms of α-crystallinopathy and its therapeutic strategy.

α-B-Crystallin (CryAB, gene map locus: 11q22.3-q23.1) is a member of the small heat shock protein (HSP) family, a group of proteins that prevent protein aggregation upon exposure of a cell to heat and/or restore the biological activity of cell substrates. The missense mutation and the deletion mutation of CryAB can cause various forms of muscular disorder, including restrictive, hypertrophic, and dilated cardiomyopathies, heart failure, and skeletal muscle weakness. Collectively, these diseases constitute a rare autosomal-dominant inherited disorder called α-crystallinopathy (crystallinopathy), also known as desmin-related cardiomyopathy. The disease is a misfolded protein-related disease characterized by the formation of insoluble protein aggregates consisting of the CryAB protein in the patient's cardiomyocytes and skeletal myocytes. The details of crystallinopathy are unclear at the present time; what has been discovered concerning the disease mechanisms underlying crystallinopathy has been through experiments with genetically modified mice such as the CryAB knockout mouse and various mutant CryAB transgenic (TG) mice. Crystallinopathy can be recapitulated in TG mice by expressing the mutant CryAB Arg120Gly (R120G) protein, a causal mutation of crystallinopathy, specifically in the cardiomyocytes. CryAB R120G causes perinuclear formation of aggresomes containing preamyloid oligomer intermediates, which are wellknown as a primary toxic species in neurodegenerative disease. This suggests that crystallinopathy caused by the CryAB mutation could be considered one of the aggresomal and amyloid-related diseases. Moreover, recent findings have indicated that enhancement of HSP induction and inhibition of apoptotic cell death by mitochondrial protection may be a new therapeutic strategy for patients with crystallinopathy.