Neurociencias.artículos

Novel in-frame variant in DES (p.Glu353dup) causes myofibrillar myopathy: clinical, in silico and functional studies

2025-12-31T00:00:00Z

Novel in-frame variant in DES (p.Glu353dup) causes myofibrillar myopathy: clinical, in silico and functional studies Castañeda, Sheila; Amín, Guadalupe; Freiberger, María Inés; Zabalegui, Federico; Renes, Sol; Fernández Gamba, Ágata; Rosa, Alberto Luis; Cejas, Claudia Patricia; Pastor Rueda, José Manuel; Waisman, Ariel; Ferreiro, Diego; Sevlever, Gustavo Emilio; Miriuka, Santiago; Moro, Lucía Natalia Background: Desmin (DES) is a major intermediate filament protein involved in the structural integrity and function of striated muscles. Pathogenic mutations in DES are predominantly missense variants, causing isolated cardiomyopathy and combinations of myopathy and cardiomyopathy. In-frame insertions are very rare and usually classified as variants of uncertain significance or likely pathogenic due to limited predictive and/or experimental evidence. Methods: This study describes a novel heterozygous in-frame insertion in exon 6 of DES (RefSeq NM_001927.4:c.1059_1061dup) identified in an Argentine family with myofibrillar myopathy (MFM). This mutation results in the duplication of a glutamic acid residue at position 353 (NP_001918.3:p.(Glu353dup)), in the 2B subdomain of the central rod domain. Clinical, computational and functional analyses were performed to study the pathogenicity of this variant. Results: Clinically, the index patient exhibited hallmark MFM features, including progressive muscle weakness, atrophy and fatty muscle replacement. In silico analyses of molecular dynamics revealed that p.Glu353dup alters DES dimer assembly by stabilising an aberrant coiled-coil conformation, a mechanism not previously proposed for DES mutations. Functional studies in HEK293T cells and C2C12 myocytes suggested that the p.Glu353dup variant induces aberrant DES aggregation, confirming its detrimental effect on filament organisation. Conclusion: These findings are consistent with the idea that p.Glu353dup is a pathogenic variant, supported by clinical studies, in silico protein modelling and functional evidence, highlighting the impact of in-frame insertions on DES filament homeostasis. By providing computational and experimental evidence, this study expands our understanding of desminopathies and offers new perspectives for pathogenicity assessment of uncertain DES variants.

Capacity building in dementia research: insights from the World Young Leaders in Dementia

2025-12-01T00:00:00Z

Capacity building in dementia research: insights from the World Young Leaders in Dementia Morello-García, Florentina; Corvalán, Nicolás; Llibre-Guerra, Jorge; Arruabarrena, Micaela; Clarens, María Florencia; Keller, Greta; De Los Santos, Loana; Martin, María Eugenia; Schaffer Aguzzoli, Cristiano; Allegri, Ricardo Francisco; Amaral, Livia; Ardohain Cristalli, Carolina; Bellaver, Bruna; Ngozi Best, Merci; Bloomquist, Madeleine; Chen, Kevin; Surace, Ezequiel Ignacio; Wilks, Hannah; Zimmer, Eduardo; Crivelli, Lucía; Hernández, Micaela Anahí; Magrath Guimet, Nahuel Early-career researchers from low- and middle-income countries face systemic barriers to professional development and leadership growth. This article presents results from an initiative led by the World Young Leaders in Dementia (WYLD), including a leadership-focused session at the Alzheimer's Association International Conference 2024 and a global survey completed by 130 dementia researchers from 17 countries. The survey explored five capacity-building domains critical for leadership development. Over half of the survey respondents stated that scientific research in their country was not prioritized in public policy. Additionally, only 39% report holding full-time academic positions. The most cited challenges included lack of funding sources, training opportunities, and physical workspace. These findings highlight the urgent need to invest in research, training, and infrastructure to support future scientific leaders. As dementia incidence rises, prioritizing capacity building is essential to ensure global equity in research. HIGHLIGHTS: Early-career dementia researchers face major barriers, especially in LMICs. A networking session and a global survey explored capacity-building needs in dementia research. Key obstacles: lack of funding, training, workspace, and protected research time. Leadership development is a critical component of sustainable research capacity.

Thyrotropin Modulates Calcium Handling and Contractility in Adult Cardiac Myocytes

2025-10-15T00:00:00Z

Thyrotropin Modulates Calcium Handling and Contractility in Adult Cardiac Myocytes Sepúlveda, Marisa; Racioppi, Florencia; Burgos, Juan Ignacio; Murillo, Alexandra; Fernandez-Ruocco, Julieta; Gonano, Luis; Neiman, Gabriel; Miriuka, Santiago Gabriel; Fellet, Andrea; Casis, Oscar; Medei, Emiliano; Colareda, German; Vila Petroff, Martín Hypothyroidism is an independent risk factor for cardiovascular disease and, if chronically sustained, leads to myocardial contractile dysfunction resulting in heart failure. However, the subcellular mechanisms underlying contractile dysfunction are not completely understood. It has been suggested that abnormal gene expression in the myocardium triggered by decreased thyroid hormone plasma levels reduces the expression of sarco-/endoplasmic reticulum calcium ion (Ca2+) adenosine triphosphatase (SERCA), resulting in slower sarcoplasmic reticulum (SR) Ca2+ uptake, a decrease in SR Ca2+ content and reduced SR Ca2+ release that mediates contractile dysfunction [1]. However, in addition to the decrease in thyroid hormones, hypothyroidism is characterised by increased thyrotropin (TSH) levels. Interestingly, subclinical hypothyroidism, which is defined by increased TSH with normal T3 and T4 levels, is also associated with altered contractile dysfunction [2], suggesting that TSH could contribute to reduced contractility observed in hypothyroidism. However, whether and how TSH impacts adult cardiac myocyte contractile function has never been addressed. This study aims to investigate whether TSH affects Ca2+ dynamics, Ca2+ handling protein expression, and contractile function in adult rat cardiac myocytes and in human-induced pluripotent stem cell-derived cardiac myocytes.

Gender-specific associations between metabolic dysfunction-associated fatty liver disease with atherosclerosis, inflammation, and eating habits

2025-11-11T00:00:00Z

Gender-specific associations between metabolic dysfunction-associated fatty liver disease with atherosclerosis, inflammation, and eating habits Rodriguez-Granillo, Gaston A.; Poggio, Rosana; Rubilar, Alejandra B.; Garron-Arias, Sarah Y.; Solari, Claudia; La Greca, Alejandro; Luzzani, Carlos; Fontana, Lucia; Arnone, Carolina V.; Ingino, Carlos; Miriuka, Santiago Gabriel Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) has multifactorial pathogenesis. Given its close relationship with dietary habits, and the need for improved geographical representation and sex discrimination, we explored the relationship between MAFLD with eating habits, systemic inflammation, and coronary atherosclerosis within a Latin American cohort. Methods: We included asymptomatic subjects between 30 and 75 years old who underwent a non-contrast, ECG-gated cardiac CT. The presence of MAFLD was defined as hepatic steatosis and at least one of: overweight/obesity, type 2 diabetes mellitus, or evidence of metabolic dysregulation. We also evaluated coronary artery calcification (CAC), laboratory, ECG, and cardiac chamber dimensions. Results: We included 799 patients (mean age 57.4 ± 10.4). Both men and women with MAFLD showed higher HbA1C (p < 0.0001) and triglyceride (p < 0.0001), and lower HDL-C (p < 0.01) levels, and larger cardiac chambers (p < 0.0001); whereas MAFLD was associated with hs-CRP levels (p < 0.0001), CAC (p < 0.01), heart rate (p = 0.002), longer QRS duration (p < 0.01) only among women. Dietary habits related to MAFLD included processed meat (p < 0.01), meat (p < 0.05), sugar-free soft beverages (p < 0.0001), and soft beverages (p < 0.01) among women, whereas men with MAFLD showed lower dairy product consumption (p < 0.01). At multivariate analysis, age (p < 0.0001), BMI (p < 0.01), HbA1C, total cholesterol, triglyceride, and LDL-C levels (all p < 0.0001), processed meat (p < 0.01), and sugar-free soft beverages (p < 0.05) were independently associated with MAFLD in women; and age (p < 0.01), BMI (p < 0.0001), HbA1C (p < 0.05), and triglycerides (p < 0.0001) in men. Conclusions: In this comprehensive Latin American cohort of asymptomatic subjects, we identified a more consistent relationship between MAFLD and a worsening cardiometabolic phenotype among women.