ORCID
0000-0002-3828-9562
Date of Award
5-9-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Rare genetic mutations in proteins expressed in cardiomyocytes lead to proteotoxic cardiomyopathies which are characterized by widespread protein-aggregate pathology. However, the mechanistic link between proteotoxicity and protein-aggregates in the more common ischemic cardiomyopathy remains unclear. Our study revealed the mis-localization of desmin, actin, and α-actinin to protein-aggregates in the myocardium of patients with ischemic cardiomyopathy and in mouse hearts undergoing post-myocardial infarction ventricular remodeling. These findings mimic observations in autosomal-dominant cardiomyopathy resulting from the R120G mutation in the chaperone protein CRYAB where desmin is mis-localized into the aggregates. Importantly, we observed increased phosphorylation of CRYAB at serine-59 (pS59-CRYAB) and its accumulation in the NP40-insoluble aggregate-rich fraction. Further investigation showed that CRYAB undergoes phase separation, and mimicking phosphorylation at serine-59 with an aspartate substitution reduced the fluidity of CRYAB condensates, promoting protein-aggregate formation and increased cell death. Conversely, substituting serine-59 with alanine, by preventing phosphorylation, restored the fluidity of CRYAB condensates and reduced protein aggregation. Moreover, introducing a phospho-deficient S59A mutation, but not the phospho-mimetic S59D mutation, at the CRYAB locus in mice rescued adverse left ventricular remodeling after ischemia reperfusion injury. Treatment with 25-Hydroxycholesterol attenuated serine-59 phosphorylation, increasing the fluidity of R120G-CRYAB condensates, and ameliorating post-myocardial infarction cardiac dysfunction. Experimental interventions aimed at preventing aggregate formation or promoting disaggregation exacerbated post-myocardial infarction cardiomyopathy, highlighting the importance of pS59CRYAB sequestration in aggregates to attenuate disease progression. These findings suggest that modulating CRYAB phase separation could offer a promising approach to mitigating ischemic cardiomyopathy.
Language
English (en)
Chair and Committee
Abhinav Diwan
Recommended Citation
Islam, Md Moydul, "αB-Crystallin Phosphorylation Induces a Condensatopathy to Worsen Post-Myocardial Infarction Cardiomyopathy" (2024). Arts & Sciences Electronic Theses and Dissertations. 3029.
https://openscholarship.wustl.edu/art_sci_etds/3029