Investigations on the structural and functional basis of desminopathy

• Applicant: Privatdozent Dr. Harald Bär
• Subject Area: Cardiology, Angiology
• Term: from 2008 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 72004690

Mutations in the cytoskeletal intermediate filament (IF) protein desmin cause a severe form of myofibrillar myopathy named desminopathy. For this disease entity, cardiac involvement is the leading cause of death. In cardiomyocytes, the extra-sarcomeric cytoplasmic cytoskeleton is composed of microtubules (tubulin), microfilaments (γ-actin) and IFs (desmin). The gene inactivation of the muscle-specific desmin gene has demonstrated that desmin IFs are critically involved in the stabilisation of the cellular architecture against mechanical forces. This property is essential for the working muscle as in desmin-knockout mice the heart ruptures during prolonged exercise. In addition to mechanically stabilizing the individual myocyte, proper positioning of the nucleus and mitochondria as well as mechanotransduction and mechanosensing do indeed depend on a functional desmin cytoskeleton.Since we are only beginning to understand these fundamental properties at a molecular level, the proposed project aims to establish the role of desmin for proper myocyte function by making use of a detailed molecular as well as physiological analysis of the influence of disease-causing desmin mutations on cardiomyocyte function. In particular, we hypothesize that mutations in desmin can give rise to: 1) altered biophysical filament and network properties, thus compromising desmin’s role in mechanotransduction and mechanosensing (alteration of intrinsic filament properties), and 2) altered binding properties to associated proteins, thus compromising vital interconnections of the desmin cytoskeleton to subcellular components (alteration of extrinsic filament properties).We will define the biophysical properties of filaments by investigating the mechanical behaviour of single filaments and filaments in bulk solution. In parallel, binding characteristics of wild type as well as mutant desmin proteins to recognized cellular binding partners such as the chaperon αB-crystallin, desmoplakin, plectin and to organelles such as mitochondria will be investigated. By establishing a zebra fish model of desminopathy we ultimately aim at understanding the mechanisms underlying the development of an experimental desminopathy as caused by overexpression of desmin mutants in a living organism.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Harald Herrmann