Related Experiment Video
Updated: Jun 13, 2025
A Cryoinjury Model to Study Myocardial Infarction in the Mouse
Published on: September 19, 2019
Phosphorylation of CRYAB Induces a Condensatopathy to Worsen Post-Myocardial Infarction Left Ventricular Remodeling
Abstract:
Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phospho-mimetic mutation of serine-59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity, and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knock-in was sufficient to induce desmin mis-localization and myocardial protein aggregates, while S59A CRYAB knock-in rescued left ventricular systolic dysfunction post-myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine-59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.
Insights
Protein aggregates in ischemic cardiomyopathy are linked to CRYAB protein phosphorylation. Targeting this phosphorylation pathway offers a potential therapeutic strategy for heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Protein Biochemistry
Background:
- Protein aggregates are implicated in rare heart diseases, but their role in common heart failure syndromes is unclear.
- Desmin and sarcomeric protein mis-localization to aggregates occurs in human ischemic cardiomyopathy and post-myocardial infarction mouse models.
Purpose of the Study:
- To investigate the role of the chaperone protein CRYAB and its phosphorylation in ischemic cardiomyopathy.
- To explore CRYAB phosphorylation-induced condensatopathy as a therapeutic target for heart failure.
Main Methods:
- Analysis of human and mouse heart tissues with ischemic cardiomyopathy and post-myocardial infarction remodeling.
- Biochemical fractionation to assess protein partitioning into insoluble aggregates.
- Generation and analysis of knock-in mouse models with specific CRYAB mutations (S59D and S59A).
- Assessment of CRYAB condensate properties, protein aggregation, cell death, and cardiac function.
Main Results:
- Phosphorylation of CRYAB at serine-59 increases its partitioning into insoluble aggregates in both human and mouse hearts.
- CRYAB S59D mutation mimics disease-causing mutations, leading to reduced condensate fluidity, increased aggregation, and cell death.
- CRYAB S59A mutation restores condensate fluidity, reduces aggregation, and protects against cell death.
- S59D CRYAB knock-in mice exhibit desmin mis-localization and myocardial aggregates; S59A CRYAB knock-in mice show improved cardiac function post-myocardial infarction.
- 25-Hydroxycholesterol reduces CRYAB phosphorylation and mitigates adverse cardiac remodeling post-myocardial infarction.
Conclusions:
- CRYAB phosphorylation at serine-59 drives protein aggregation and contributes to ischemic cardiomyopathy.
- Targeting CRYAB phosphorylation-induced condensatopathy presents a promising therapeutic avenue for treating ischemic heart failure.
More Related Videos
14:35Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs
Published on: April 17, 2021
12:45Benefits of Cardiac Resynchronization Therapy in an Asynchronous Heart Failure Model Induced by Left Bundle Branch Ablation and Rapid Pacing
Published on: December 11, 2017
Related Concept Videos
01:02Phosphorylation
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
01:27Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
02:54Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...