UNDERSTANDING THE PATHOBIOLOGY OF MUTANT BAG3: PROTEOTOXICITY, MITOCHONDRIAL DYSFUNCTION AND IMPLICATIONS FOR THE TREATMENT OF RARE BAG3-RELATED CARDIOMYOPATHIES

The molecular co-chaperone Bcl2-associated athanogene 3 (Bag3) is a critical component of protein quality control (PQC) systems in the heart. Bag3, which includes multiple protein binding domains, interacts in complex with numerous chaperones and clients to regulate protein folding, degradation, and response to intracellular protein aggregation. Mutations in Bag3 are associated with human cardiac myopathies, including a proline to leucine substitution at position 209 (P209L), which causes a particularly severe childhood-onset cardiomyopathy. Currently, the molecular mechanisms by which the Bag3P209L mutation results in cardiomyopathy remain elusive and no therapies exist for Bag3-related cardiomyopathies. In this dissertation, I utilize a cardiac-specific Bag3P209L transgenic (Tg+) mouse model to investigate the signaling mechanisms that underlie the pathobiology of Bag3-related cardiomyopathy. Bag3P209L Tg+ hearts exhibit cardiac pre-amyloid oligomers (PAOs) and protofibrils, known drivers of neurodegenerative proteinopathies, which have recently been revealed to drive cardiac proteotoxicity and disfunction in models of cardiomyopathy. Next, I identify proteotoxic p38 MAPK signaling as a central regulator of PAO-induced PQC collapse in Bag3P209L Tg+ mice and demonstrate that inhibitors of p38 signaling are able to reduce PAOs and insoluble protein aggregation leading to complete restoration of cardiac function in treated Bag3P209L Tg+ mice. Finally, I focus on mitochondrial impairment in Bag3P209L Tg+ hearts and identify mitochondrial fragmentation, NAD depletion, and protein hyperacetylation as features of Bag3P209L related pathobiology. Together, these studies provide novel insights into the pathobiology of Bag3-related cardiomyopathies and identify p38 MAPK inhibition as a promising therapeutic intervention to treat Bag3-related cardiomyopathy.Doctor of Philosoph