Aggregating instead of stabilizing: New insights into the mechanisms of heart disease

Malformed desmin proteins aggregate with intact proteins of the same kind, thereby triggering skeletal and cardiac muscle diseases, the desminopathies. This was discovered by researchers from the RUB Heart and Diabetes Center NRW in Bad Oeynhausen led by PD Dr. Hendrik Milting in an interdisciplinary research project with colleagues from the universities in Karlsruhe, Würzburg and Bielefeld. They report in the Journal of Biological Chemistry.

Desmin normally forms stabilizing filaments inside of the cells. Different mutations in the DES gene, which contains the blueprint for the , induce different muscle diseases. Since chromosomes are always present in pairs, each cell has two DES genes on two different chromosomes. The desminopathies break out even if only one of the DES genes is mutated. With Photo Activation Localization Microscopy (PALM), the interdisciplinary team led by Dr. Milting revealed the mechanism behind this.

If one DES gene is mutated and one intact, a cell produces both malformed and normal proteins. Since not only the mutant desmin proteins clump together, but also the intact exemplars are incorporated into the aggregates, one defective DES gene is enough to trigger the disease. Using the PALM microscope, the researchers attach two different fluorescent molecules to the mutant and the intact proteins. They can turn these markers on and off by laser, effectively flashing them. From the "snapshots" of the intact and the mutated proteins, the computer then calculates a joint picture on which both protein variants can be seen. PALM is a novel microscopy technique that can achieve ten times higher resolution than conventional light microscopy.

In the next step, the research group would like to find out how mutations in the DES gene trigger what is termed arrhythmogenic right ventricular cardiomyopathy, ARVC for short. This rare heart muscle disease is characterized by a severe defect – especially to the right ventricle – and by rhythm problems that can lead to sudden cardiac death due to defects in the cell-cell contacts.

More information: A. Brodehl et al. (2012): Dual-color photoactivation localization microscopy of cardiomyopathy associated desmin mutants, Journal of Biological Chemistry, doi: 10.1074/jbc.M111.313841

add to favorites email to friend print save as pdf

Related Stories

Researchers link gene mutations to Ebstein's anomaly

Feb 16, 2011

Ebstein's anomaly is a rare congenital valvular heart disease. Now, in patients with this disease, researchers of the Academic Medical Center Amsterdam in the Netherlands, the University of Newcastle, UK and the Max Delbrück ...

Parkinson's mutation stunts neurons

Nov 22, 2006

Mutations in a key brain protein known to underlie a form of Parkinson's disease wreaks its damage by stunting the normal growth and branching of neurons, researchers have found. They have pinpointed the malfunction of the ...

New gene linked to muscular dystrophy

Aug 10, 2009

Muscular dystrophy, a group of inherited diseases characterized by progressive skeletal muscle weakness, can be caused by mutations in any one of a number of genes. Another gene can now be added to this list, as Yukiko Hayashi ...

Recommended for you

Team untangles the biological effects of blue light

9 hours ago

Blue light can both set the mood and set in motion important biological responses. Researchers at the University of Pennsylvania's School of Medicine and School of Arts and Sciences have teased apart the ...

Mouse model provides new insight in to preeclampsia

10 hours ago

Worldwide, preeclampsia is a leading cause of maternal deaths and preterm births. This serious pregnancy complication results in extremely high blood pressure and organ damage. The onset of preeclampsia is associated with ...

User comments