Abstract 2823: Expression of an Amyloidogenic Polyglutamine (PQ83) Peptide Causes Apoptosis and Heart Failure
Introduction: Pre-amyloid oligomers (PAOs), the entities believed to cause toxicity in Alzheimer’s and other neurodegenerative diseases, are also observed in the cardiomyocytes of many human heart failure samples. PAOs were also characterized in the cardiomyocytes of mouse models of Desmin-Related Cardiomyopathy; these models display high levels of apoptosis and heart failure. PAOs are a diverse group of proteins or peptide fragments that differ in sequence, but share a common conformation-dependent protein structure, which may underlie a shared pathogenic mechanism.
Hypothesis: Cardiomyocyte-specific expression of PAOs is toxic and capable of causing heart failure.
Methods: We ectopically expressed a PAO-genic polyglutamine peptide in mouse cardiomyocytes to test its pathogenicity. Although, short polyglutamine tracts are benign, longer tracts cause a number of neurodegenerative disorders, including Huntington’s disease. Cardiomyocyte-specific expression of either a PAO-genic peptide, consisting of 83 polyglutamine repeats (PQ83), or a nonamyloidogenic 19 polyglutamine repeat (PQ19) was driven using the alpha myosin heavy chain promoter. Both constructs were HA tagged.
Results: Despite numerous injections, only a single viable PQ83 line was obtained; this line had extremely low levels of expression. PQ83 hearts showed significantly reduced shortening fractions and cardiac dilation by 5 months. At 7 months all PQ83 mice were dead. In contrast, PQ19 mice showed high levels of expression in the cardiomyocytes with normal cardiac function and morphology. Immunohistochemical analysis of PQ83 heart sections confirmed PQ83 expression and the presence of PAOs. Apoptotic processes were also active in PQ83 heart failure as indicated by a marked increase in the number of TUNEL-positive nuclei. The data confirm that cardiomyocyte autonomous expression of a PAO-genic PQ83 peptide is toxic and sufficient to cause heart failure.