Untangle a Broken Heart via Janus Kinase 1
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Protein homeostasis and quality control, as balanced by synthesis and degradation, is critical to cellular health and normal cardiac function. Similar to amyloid-related neurodegenerative diseases, the familial forms of amyloid cardiomyopathy are characterized by protein aggregate accumulation in cardiomyocytes. These protein aggregates trigger proteotoxicity in cardiomyocytes, leading to cardiac remodeling and dysfunction.1 Beyond these familial forms of cardiomyopathies, protein aggregation is also a common and perhaps functionally significant pathological feature in the diseased hearts induced by a variety of pathological stressors, including pressure overload and ischemia.2,3 Therefore, understanding the pathogenic mechanisms of cardiac proteotoxicity induced by protein aggregation in cardiomyocytes could lead to significant progress to develop potential therapeutic interventions, not only for the rare cases of amyloid cardiomyopathies but also for the common forms of heart failure in general.
Article, see p 604
In this issue, McLendon et al4 from Robbins’s laboratory performed an unbiased genome-wide screening to identify genes affecting protein aggregation in primary cardiomyocytes. Taking advantage of a previously established αB-Crystallin mutant protein (CryABR120G) which possesses a strong propensity to form desmin-related protein aggregates in cardiomyocytes,5,6 they developed a high-throughput screening platform to measure protein aggregation quantitatively based on fluorescent signal intensity from the exogenously expressed GFP (green fluorescent protein) CryAB …