To the Heart of IFs Function: Do they Aggregate on Purpose?

Background: One of the molecular hallmarks in the development of heart failure (HF) is loss of ultrastructure within the cardiac myocyte. In addition, HF is increasingly recognized as a proteinopathy characterized by the accumulation of misfolded proteins similar to Alzheimer and Parkinson disease. However, despite its increasing prevalence and poor prognosis, the advances in the pharmacological treatment of HF have been limited, highlighting an urgent need for the discovery of new therapeutic targets. We reported a consistent accumulation of mono-phosporylated desmin in experimental and clinical models of HF. We also demonstrated how mono-phosphorylated desmin is more prone to cleavage and aggregation in isolated cardiac myocytes. Therefore, if on the one hand desmin cleavage could easily explain the loss of a cardiac myocyte\u2019s ultrastructure, its high abundance and propensity to aggregate make it an ideal candidate as the seed generating pre-amyloid-oligomers (PAOs) and amyloid fibrils in the heart. Methods: Using a combination of novel and established protein biochemistry techniques, we aimed at demonstrating desmin\u2019s identity as the seed starting the nucleation process which leads to the formation of cardiac PAOs and amyloid fibrils. Results: Desmin displayed common features shared by other established PAOs and fibrils (e.g. tinctorial properties) in experimental and clinical models of HF. Conclusions: The inherent propensity of intermediate filaments to aggregate, combined with the use of cardiac tissue as a model for repeated mechanical stretch, suggest that intermediate filaments aggregation could be used as a way to dissipate/scavange mechanical as well as chemical stress. We will therefore use the highly organized structure of cardiac myocytes to infer IFs function in mammalian cells

Is Desmin Propensity to Aggregate Part of its Protective Function?

Desmin is the major protein component of the intermediate filaments (IFs) cytoskeleton in muscle cells, including cardiac. The accumulation of cleaved and misfolded desmin is a cellular hallmark of heart failure (HF). These desmin alterations are reversed by therapy, suggesting a causal role for the IFs in the development of HF. Though IFs are known to play a role in the protection from stress, a mechanistic model of how that occurs is currently lacking. On the other hand, the heart is uniquely suited to study the function of the IFs, due to its inherent, cyclic contraction. That is, HF can be used as a model to address how IFs afford protection from mechanical, and possibly redox, stress. In this review we provide a brief summary of the current views on the function of the IFs, focusing on desmin. We also propose a new model according to which the propensity of desmin to aggregate may have been selected during evolution as a way to dissipate excessive mechanical and possibly redox stress. According to this model, though desmin misfolding may afford protection from acute injury, the sustained or excessive accumulation of desmin aggregates could impair proteostasis and contribute to disease

Cofilin-2 Phosphorylation and Sequestration in Myocardial Aggregates Novel Pathogenetic Mechanisms for Idiopathic Dilated Cardiomyopathy

AbstractBackgroundRecently, tangles and plaque-like aggregates have been identified in certain cases of dilated cardiomyopathy (DCM), traditionally labeled idiopathic (iDCM), where there is no specific diagnostic test or targeted therapy. This suggests a potential underlying cause for some of the iDCM cases.ObjectivesThis study sought to identify the make-up of myocardial aggregates to understand the molecular mechanisms of these cases of DCM; this strategy has been central to understanding Alzheimer’s disease.MethodsAggregates were extracted from human iDCM samples with high congophilic reactivity (an indication of plaque presence), and the findings were validated in a larger cohort of samples. We tested the expression, distribution, and activity of cofilin in human tissue and generated a cardiac-specific knockout mouse model to investigate the functional impact of the human findings. We also modeled cofilin inactivity in vitro by using pharmacological and genetic gain- and loss-of-function approaches.ResultsAggregates in human myocardium were enriched for cofilin-2, an actin-depolymerizing protein known to participate in neurodegenerative diseases and nemaline myopathy. Cofilin-2 was predominantly phosphorylated, rendering it inactive. Cardiac-specific haploinsufficiency of cofilin-2 in mice recapitulated the human disease’s morphological, functional, and structural phenotype. Pharmacological stimulation of cofilin-2 phosphorylation and genetic overexpression of the phosphomimetic protein promoted the accumulation of “stress-like” fibers and severely impaired cardiomyocyte contractility.ConclusionsOur study provides the first biochemical characterization of prefibrillar myocardial aggregates in humans and the first report to link cofilin-2 to cardiomyopathy. The findings suggest a common pathogenetic mechanism connecting certain iDCMs and other chronic degenerative diseases, laying the groundwork for new therapeutic strategies

Casi Clinici in Biochimica Metabolica

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Obesity-induced cardiac dysfunction: pre-natal vs. post-natal nurture

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