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Pflugers Arch. 2018 Aug 14. doi: 10.1007/s00424-018-2194-0. [Epub ahead of print]

Untying the knot: protein quality control in inherited cardiomyopathies.

Author information

1
Amsterdam UMC, Department of Physiology, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, O2 building 11W53, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands. l.dorsch@vumc.nl.
2
Amsterdam UMC, Department of Physiology, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, O2 building 11W53, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands. m.schuldt@vumc.nl.
3
Amsterdam UMC, Department of Physiology, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, O2 building 11W53, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.

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.

KEYWORDS:

Autophagy; Cardiomyopathy; Heat shock proteins; Protein quality control; Sarcomeric mutation; Ubiquitin-proteasome system

PMID:
30109411
DOI:
10.1007/s00424-018-2194-0

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