Untying the knot: protein quality control in inherited cardiomyopathies

Larissa M. Dorsch, Maike Schuldt, Dora Knežević, Marit Wiersma, Diederik W.D. Kuster, Jolanda van der Velden, Bianca J.J.M. Brundel

Research output: Contribution to journalReview articleAcademicpeer-review

12 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)795-806
Number of pages12
JournalPflugers Archiv European Journal of Physiology
Issue number5
Early online date14 Aug 2018
Publication statusPublished - 1 May 2019


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

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