Desmin related disease: a matter of cell survival failure

Abstract

Maintenance of the highly organized striated muscle tissue requires a cell-wide dynamic network that through interactions with all vital cell structures, provides an effective mechanochemical integrator of morphology and function, absolutely necessary for intra- and intercellular coordination of all muscle functions. A good candidate for such a system is the desmin intermediate filament cytoskeletal network. Human desmin mutations and post-translational modifications cause disturbance of this network, thus leading to loss of function of both desmin and its binding partners, as well as potential toxic effects of the formed aggregates. Both loss of normal function and gain of toxic function are linked to mitochondrial defects, cardiomyocyte death, muscle degeneration and development of skeletal myopathy and cardiomyopathy.

Nebulette is a powerful cytolinker organizing desmin and actin in mouse hearts

“…We found abnormally high actin levels, suggesting a functional dependence among these three proteins in heart. Remarkably, Des −/− knockout and transgenic nebulette Q128R mice share atypical lysosomes, mitochondria, and intercalated disks (Bang and Chen, 2015; Capetanaki et al , 2015). To suggest that desmin–nebulette partnership may account for some of these defects in cardiomyocytes is tempting and requires further study.…”

“…An anomaly of the desmin–nebulette interaction caused by a glutamic to aspartic acid mutation in desmin at position 245 underlies a human desminopathy (Vrabie et al , 2005; Strach et al , 2008; Conover et al , 2009). Desminopathies belong to a heterogeneous genetic disease entity, termed myofibrillar myopathies (MFMs), which are caused by at least 40 distinct desmin mutations and are characterized by the formation of desmin aggregates in striated muscle (van Spaendonck-Zwarts et al , 2011; Claeys and Fardeau, 2013; Clemen et al , 2013; Capetanaki et al , 2015). …”

“…parallel α-helices (Chernyatina et al , 2015; Koster et al , 2015). Given the broad expression of IF proteins and the diverse distribution of IF proteins in the body, it has been proposed that their tissue-specialized functions may result from their interaction with tissue-specific binding partners (Herrmann and Aebi, 2004; Capetanaki et al , 2015; Kornreich et al , 2015; Koster et al , 2015). …”

Desmin and αB-crystallin interplay in the maintenance of mitochondrial homeostasis and cardiomyocyte survival

“…The desmin scaffold is a primary target for cardiomyopathy and heart failure both in mice and humans (Goldfarb et al, 1998;Capetanaki et al, 2007Capetanaki et al, , 2015. Mice deficient for desmin develop both skeletal and myocardial defects that are strongly linked to impaired mitochondrial morphology and function (Milner et al, 1996(Milner et al, , 1999(Milner et al, , 2000Li et al, 1996;Papathanasiou et al, 2015).…”

Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18

“…We showed that desmin, the muscle-specific IF protein, is a major target in TNFα-induced cardiomyopathy 21,22 . Specifically, desmin is cleaved by TNF-α-induced caspase-6, loses its proper ID localization and forms aggregates.…”