Abstract 258: Human 450delACryAB Overexpression Associated with Protein Aggregation Uncovers a Novel Mechanism for Inheritable Myofibrillar-Sparing Cardiomyopathy in Mice
Desmin-related cardiomyopathy (DRC) belongs to the family of myofibrillar diseases characterized by the presence of toxic desmin-positive aggregates and degeneration at Z-disk structures. DRC has been linked to the mutations in the desmin, αBcrystallin (CryAB), or myotilin genes. Several human CryAB mutations cause multisystem disorders and experimental models of R120GCryAB in transgenic mice strikingly recapitulate similar phenotype observed in patients. In this context, we have generated the 450delACryAB linked to inheritable cataracts in neonatal rat cardiomyocytes and mice hearts. 450delACryAB formed aggregates or aggresomes, and recruited HSP25 into the insoluble fraction in the cardiomyocytes. However, heart-specific 450delA CryAB overexpression neither causes desmin-related cardiomyopathy nor exacerbates pressure overload-induced hypertrophy. To our knowledge, this is the first report of compensation to protein aggregates formation abrogates the development of cardiomyopathy and suggests possible insights into disease-specific susceptibility and resistance. We found that there are several different characteristics between 450delACryAB and R120GCryAB. First, 450delACryAB formed much less soluble oligomers than R120GCryAB in cardiomyocytes, and translocated almost into the insoluble fraction when overexpressing in the hearts. Secondly, 450delACryAB aggregates displayed small pattern without either disturbance of desmin striated network or sequestration of desmin into the insoluble fraction, although 450delACryAB interacts with desmin in the heart. Thirdly, doxycycline treatment did not suppress 450delACryAB aggregates. Nonetheless, 450delACryAB aggregates caused the accumulation of ubiquitinated proteins and subsequently upregulated autophagy activity in mice heart, which is similar to R120GCryAB aggregates. The interaction of 450delACryAB with AKT, p62 and Beclin 1 might contribute to impaired UPS dysfunction and activation of autophagy. The findings reported here suggest that such differences contribute to the variable penetrance and pathogenesis in humans.
- © 2012 by American Heart Association, Inc.