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Untying the knot: protein quality control in inherited cardiomyopathies
Larissa M Dorsch1, Maike Schuldt2, Dora Knežević3
1Amsterdam UMC, Department of Physiology, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, O2 building 11W53, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands. l.dorsch@vumc.nl.
Insights
Inherited cardiomyopathies stem from sarcomeric gene mutations. Loss of protein quality control (PQC) contributes to disease, highlighting PQC as a therapeutic target for preventing cardiac dysfunction.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Cellular Proteostasis
Background:
- Inherited cardiomyopathies, often caused by sarcomeric gene mutations, are significant global health issues.
- Current treatments focus on early detection, lacking strategies to prevent disease progression.
- Impaired protein quality control (PQC) and cellular proteostasis are increasingly recognized in disease pathology.
Purpose of the Study:
- To review recent findings on proteostasis derailment in inherited cardiomyopathies.
- To focus on the role of sarcomeric gene mutations in PQC disruption.
- To explore potential therapeutic applications targeting PQC.
Main Methods:
- Review of current literature on protein quality control mechanisms.
- Analysis of studies linking sarcomeric mutations to proteostasis.
- Examination of potential therapeutic strategies for inherited cardiomyopathies.
Main Results:
- Loss of PQC, including impaired heat shock proteins, ubiquitin-proteasome system, and autophagy, is central to cardiomyopathy pathogenesis.
- Misfolded proteins, sarcomeric protein loss, and cardiac dysfunction result from PQC derailment.
- PQC dysfunction can arise from direct mutation effects, compensatory responses, or secondary hits.
Conclusions:
- Proteostasis derailment is a key mechanism in inherited cardiomyopathies driven by sarcomeric gene mutations.
- Targeting PQC pathways offers promising therapeutic avenues to prevent or delay cardiac disease onset and progression.
Abstract:
Mutations in genes encoding sarcomeric proteins are the most important causes of inherited cardiomyopathies, which are a major cause of mortality and morbidity worldwide. Although genetic screening procedures for early disease detection have been improved significantly, treatment to prevent or delay mutation-induced cardiac disease onset is lacking. Recent findings indicate that loss of protein quality control (PQC) is a central factor in the disease pathology leading to derailment of cellular protein homeostasis. Loss of PQC includes impairment of heat shock proteins, the ubiquitin-proteasome system, and autophagy. This may result in accumulation of misfolded and aggregation-prone mutant proteins, loss of sarcomeric and cytoskeletal proteins, and, ultimately, loss of cardiac function. PQC derailment can be a direct effect of the mutation-induced activation, a compensatory mechanism due to mutation-induced cellular dysfunction or a consequence of the simultaneous occurrence of the mutation and a secondary hit. In this review, we discuss recent mechanistic findings on the role of proteostasis derailment in inherited cardiomyopathies, with special focus on sarcomeric gene mutations and possible therapeutic applications.
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