Nemaline myopathy (NM) is the most common form of congenital myopathy that results in hypotonia and muscle weakness. This disease is clinically and genetically heterogeneous, but three recently discovered genes in NM encode for members of the Kelch family of proteins. Kelch proteins act as substrate-specific adaptors for Cullin 3 (CUL3) E3 ubiquitin ligase to regulate protein turnover through the ubiquitin-proteasome machinery. Defects in thin filament formation and/or stability are key molecular processes that underlie the disease pathology in NM; however, the role of Kelch proteins in these processes in normal and diseases conditions remains elusive. Here, we describe a role of NM causing Kelch protein, KLHL41, in premyofibil-myofibil transition during skeletal muscle development through a regulation of the thin filament chaperone, nebulin-related anchoring protein (NRAP). KLHL41 binds to the thin filament chaperone NRAP and promotes ubiquitination and subsequent degradation of NRAP, a process that is critical for the formation of mature myofibrils. KLHL41 deficiency results in abnormal accumulation of NRAP in muscle cells. NRAP overexpression in transgenic zebrafish resulted in a severe myopathic phenotype and absence of mature myofibrils demonstrating a role in disease pathology. Reducing Nrap levels in KLHL41 deficient zebrafish rescues the structural and function defects associated with disease pathology. We conclude that defects in KLHL41-mediated ubiquitination of sarcomeric proteins contribute to structural and functional deficits in skeletal muscle. These findings further our understanding of how the sarcomere assembly is regulated by disease-causing factors in vivo, which will be imperative for developing mechanism-based specific therapeutic interventions.
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http://dx.doi.org/10.1093/hmg/ddz078 | DOI Listing |
Neurogenetics
January 2025
Department of Pediatrics, Erciyes University, Faculty of Medicine, Kayseri, Turkey.
The cytoskeleton, composed of microtubules, intermediate filaments and actin filaments is vital for various cellular functions, particularly within the nervous system, where microtubules play a key role in intracellular transport, cell morphology, and synaptic plasticity. Tubulin-specific chaperones, including tubulin folding cofactors (TBCA, TBCB, TBCC, TBCD, TBCE), assist in the proper formation of α/β-tubulin heterodimers, essential for microtubule stability. Pathogenic variants in these chaperone-encoding genes, especially TBCD, have been linked to Progressive Encephalopathy with Brain Atrophy and Thin Corpus Callosum (PEBAT, OMIM #604,649), a severe neurodevelopmental disorder.
View Article and Find Full Text PDFActa Parasitol
January 2025
Department of Molecular Biology and Genetics, Faculty of Arts and Science, Ordu University, Ordu, Türkiye.
Purpose: The brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae), is an invasive and a highly polyphagous species with a strong dispersal capacity. Unfortunately, there is currently no effective control method that can prevent or reduce the economic loss caused by this pest. Among natural enemies, microsporidia cause infections in insects so that they can generally shorten life span, reduce fertility and inhibit growth.
View Article and Find Full Text PDFChemistry
January 2025
University of Toronto, Chemistry, 80 St George Street, M5S 3H6, Toronto, CANADA.
The synthesis of polyferrocenyldimethylsilane-b-poly(L-glutamic acid) block copolymers was systematically explored. Rod-like and plate-like micelles were prepared from self-assembly of the block copolymers in aqueous solution with two different approaches. In a dissolution-dialysis approach, micelles were prepared by dissolving a block copolymer sample in excess aqueous base followed by the dialysis of the solution against water.
View Article and Find Full Text PDFAdv Mater
January 2025
College of Textiles, Donghua University, Shanghai, 201620, China.
Fiber-based artificial muscles are soft actuators used to mimic the movement of human muscles. However, using high modulus oxide ceramics to fabricate artificial muscles with high energy and power is a challenge as they are prone to brittle fracture during torsion. Here, a ceramic metallization strategy is reported that solves the problem of low torsion and low ductility of alumina (AlO) ceramics by chemical plating a thin copper layer on alumina filaments.
View Article and Find Full Text PDFBiophys Rev
December 2024
Randall Centre for Cell & Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, UK.
Calcium binding to troponin triggers the contraction of skeletal and heart muscle through structural changes in the thin filaments that allow myosin motors from the thick filaments to bind to actin and drive filament sliding. Here, we review studies in which those changes were determined in demembranated fibres of skeletal and heart muscle using fluorescence for in situ structure (FISS), which determines domain orientations using polarised fluorescence from bifunctional rhodamine attached to cysteine pairs in the target domain. We describe the changes in the orientations of the N-terminal lobe of troponin C (TnC) and the troponin IT arm in skeletal and cardiac muscle cells associated with contraction and compare the orientations with those determined in isolated cardiac thin filaments by cryo-electron microscopy.
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