Research Focus >Nemaline Myopathy

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nemaline myopathy (NM)

Nemaline myopathy is a congenital disease that is characterized by appearance of proteinaceous aggregates, called nemaline bodies, in a patients skeletal muscles. Depending on the type of NM and the disease causing mutation, this myopathy can be fatal.

We investigate molecular mechanisms at play in the development of this disease by using skeletal muscle specific Cullin-3 knockouts.

Cardiac and skeletal muscle cells contain two major proteolytic systems for the degradation of proteins: the ubiquitin-proteasome system (UPS) and the autophagy/lysosome system. Degradation of most cellular proteins is achieved by way of the UPS and requires tagging of substrate proteins by ubiquitin (poly-ubiquitylation) through an enzymatic cascade. Cullin-3 is one of the enzymes that forms part of the UPS.

the ubiquitin proteasome system
Figure on the ubiquitin-proteasome system. Adapted from a book chapter in "Cardiac Cytoarchitecture: How to Maintain a Working Heart-Waste Disposal and Recycling in Cardiomyocytes".

the role of Cullin-3

In our new manuscript, we outlined the role that this E3-ligase function plays for the development of nemaline myopathy in a murine model of the disease. Using mice that are deficient of Cullin-3, we define a novel molecular pathomechanism that may be at play in patients suffering from mutations in KBTBD13. The manuscript can be found at JCI Insight.

role of Cullin3 for NM

The original article can be found at JCI Insight.

Related Publications

  • Cardiac Cytoarchitecture: How to Maintain a Working Heart-Waste Disposal and Recycling in Cardiomyocytes. Jordan Blondelle & Stephan Lange. Book Chapter in Cardiac Cytoarchitecture. Edited by Elisabeth Ehler. Springer International Publishing Switzerland. 2015. ISBN: 978-3-319-15262-2 (Print) 978-3-319-15263-9 (Online). Online Version

  • Cullin E3 ligase activity is required for myoblast differentiation. Jordan Blondelle, Paige Shapiro, Andrea A. Domenighetti, Stephan Lange. JMB. 2017.

  • Cullin-3 dependent deregulation of ACTN1 represents a new pathogenic mechanism in nemaline myopathy. Blondelle J, Tallapaka K, Seto JT, Ghassemian M, Clark M, Laitila JM, Bournazos A, Singer JD, Lange S. JCI Insight. 2019 Apr 16.

Future Directions

We are currently investigating whether E3-ligases of the cullin protein family play a greater role for muscle specific protein turnover than previously anticipated. Of particular interest is the possible role that faulty cullin-3 function and accumulation of its substrates play for the development of neuromuscular diseases and cardiomyopathies.

Collaborators on this project

  • Dr. Jeffrey Singer at Portland State University, OR
  • Dr. Jane Seto at Murdoch Children's Hospital, Australia
  • Drs. Careina Wallgren-Pettersson & Katarina Pelin at the University of Helsinki, Finland
Keywords: degradation, cullin, E3-ligase, ubiquitin.