ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes
, Sonia R. Singh 1,2, Niels Pietsch 1,2, Ellen Orthey 1,2, Erda Alizoti 1,2, Josefine Busch 1,2, Alexandra Madsen 1,2, Charlotta S. Behrens 1,2, Moritz Meyer-Jens 1,2, Giulia Mearini 1,2, Marc D. Lemoine 1,2,4, Elisabeth Krämer 1,2, Diogo Mosqueira 5, Sanamjeet Virdi 6, Daniela Indenbirken 6, Maren Depke 7, Manuela Gesell Salazar 7, Uwe Völker 7,8, Ingke Braren 9, Elke Hammer 7,8, Lucie Carrier 1,2,*add
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Agapios Sachinidis
Round 1
Reviewer 1 Report
Applying 2 knock-out transgenic hiPSC lines (ACTN2wt and missense ACTN2mut allele) authors generated cardiomyocytes (hiPSC-CMs) which were functionally characterised by applying several classical states of the art molecular biology methods in combination with genomics technique. Authors demonstrated that ACTN2mut-CMs are more multinucleated, showed an increased protein aggregation and are more hypertrophic as compared to the ACTN2wt. In addition, both the ubiquitin-proteasome system and the autophagy-lysosomal pathway were more active in the ACTN2mut-CMs as compared to ACTN2wt. Furthermore, a significant reduction of sarcomere-associated protein levels was observed in ACTN2mut-CMs which explains the reduction of the force in engineered heart tissue containing ACTN2mut-CMs. Authors conclude that ACTN2mut-CMs may additionally contribute to human ACTN2-associated cardiomyopathies via induction of proteinopathy.
This is an elegant study. The manuscript is well written and the conclusions reflect the present novel findings.
Author Response
We would like to thank the reviewer for his/her very nice comments on our manuscript.
Reviewer 2 Report
This article describes a comprehensive and well-designed study elucidating the mechanism of ACTN2 mutations leading to changes in cardiomyocytes structure and function. The authors present clear and detailed characterization of ACTN2mut in hiPSC-CMs on the protein, cellular and engineered tissue level. They reveal novel mechanistic insight on the loss of protein-protein interaction as the main driver for cellular disfunction and potential disease progress.
Author Response
We would like to thank the reviewer for his/her very nice comments
