When Lamins Go Bad: Nuclear Structure and Disease
ABSTRACT Mutations in nuclear lamins or other proteins of the nuclear envelope are the root cause of a group of phenotypically diverse genetic disorders known as laminopathies, which have symptoms that range from muscular dystrophy to neuropathy to premature aging syndromes. Although precise disease mechanisms remain unclear, there has been substantial progress in our understanding of not only laminopathies, but also the biological roles of nuclear structure. Nuclear envelope dysfunction is associated with altered nuclear activity, impaired structural dynamics, and aberrant cell signaling. Building on these findings, small molecules are being discovered that may become effective therapeutic agents.
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- "Diseases caused by mutations in genes encoding nuclear lamins are generally termed laminopathies (Worman 2012). With respect to LMNA, they comprise striated muscle diseases, such as Emery- Dreifuss muscular dystrophy (EDMD) and dilated cardiomyopathy (DCM); lipodystrophic syndromes, such as familial partial lipodystrophy (FPLD); peripheral neuropathies , such as Charcot-Marie-Tooth disease; and accelerated aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS) (Schreiber and Kennedy 2013). "
ABSTRACT: The intermediate filament proteins, A- and B-type lamins, form the nuclear lamina scaffold adjacent to the inner nuclear membrane. B-type lamins confer elasticity, while A-type lamins lend viscosity and stiffness to nuclei. Lamins also contribute to chromatin regulation and various signaling pathways affecting gene expression. The mechanical roles of lamins and their functions in gene regulation are often viewed as independent activities, but recent findings suggest a highly cross-linked and interdependent regulation of these different functions, particularly in mechanosignaling. In this newly emerging concept, lamins act as a "mechanostat" that senses forces from outside and responds to tension by reinforcing the cytoskeleton and the extracellular matrix. A-type lamins, emerin, and the linker of the nucleoskeleton and cytoskeleton (LINC) complex directly transmit forces from the extracellular matrix into the nucleus. These mechanical forces lead to changes in the molecular structure, modification, and assembly state of A-type lamins. This in turn activates a tension-induced "inside-out signaling" through which the nucleus feeds back to the cytoskeleton and the extracellular matrix to balance outside and inside forces. These functions regulate differentiation and may be impaired in lamin-linked diseases, leading to cellular phenotypes, particularly in mechanical load-bearing tissues. © 2015 Osmanagic-Myers et al.; Published by Cold Spring Harbor Laboratory Press.Genes & Development 02/2015; 29(3):225-237. DOI:10.1101/gad.255968.114 · 12.64 Impact Factor
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- "Despite this fact, the precise function(s) of the nuclear lamins are not fully understood. Key clues into their molecular roles have come from the study of human lamin diseases called laminopathies, which point to roles in cellular signaling pathways as well as maintenance of nuclear architecture and NPC positioning within the NE . Larry Gerace (The Scripps Institute, USA) presented evidence that the lamin-interacting protein Lem2 may be a key integrator for cell signaling pathways during myogenesis. "
ABSTRACT: Transport of macromolecules between the cytoplasm and the nucleus is critical for the function of all eukaryotic cells. Large macromolecular channels termed nuclear pore complexes that span the nuclear envelope mediate the bidirectional transport of cargoes between the nucleus and cytoplasm. However, the influence of macromolecular trafficking extends past the nuclear pore complex to transcription and RNA processing within the nucleus and signaling pathways that reach into the cytoplasm and beyond. At the Mechanisms of Nuclear Transport biennial meeting held from October 18-23, 2013 in Woods Hole, MA, researchers in the field met to report on their recent findings. The work presented highlighted significant advances in understanding nucleocytoplasmic trafficking including how transport receptors and cargoes pass through the nuclear pore complex, the many signaling pathways that impinge on transport pathways, interplay between the nuclear envelope, nuclear pore complexes, and transport pathways, and numerous links between transport pathways and human disease. The goal of this review is to highlight newly emerging themes in nuclear transport and underscore the major questions that are likely to be the focus of future research in the field.Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 08/2014; 1843(11). DOI:10.1016/j.bbamcr.2014.08.003 · 5.30 Impact Factor
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- "In addition, the dystrophic mdx heart is characterized by a reduction in the protein lamin of the nuclear envelope complex . The reduced presence of lamin may drastically weaken the linkage between the lamin network and its associated proteins nesprin, SUN1, SUN2 and plectin at the interface between muscle nuclei and the cytoskeleton . With respect to biomarker discovery for dystrophinopathies, the proteomic identification of altered concentration levels in distinct cytoskeletal proteins suggests desmin, vimentin, tubulin and lamin as potential candidates for developing diagnostic tests for the differential analysis of muscular dystrophy. "
ABSTRACT: The optimization of large-scale screening procedures of pathological specimens by genomic, proteomic and metabolic methods has drastically increased the bioanalytical capability for swiftly identifying novel biomarkers of inherited disorders, such as neuromuscular diseases. X-linked muscular dystrophy represents the most frequently inherited muscle disease and is characterized by primary abnormalities in the membrane cytoskeletal protein dystrophin. Mass spectrometry-based proteomics has been widely employed for the systematic analysis of dystrophin-deficient muscle tissues, using patient samples and animal models of dystrophinopathy. Both, gel-based methods and label-free mass spectrometric techniques have been applied in compar- ative analyses and established a large number of altered proteins that are associated with muscle contraction, energy metabolism, ion homeostasis, cellular signaling, the cytoskeleton, the extracellular matrix and the cellular stress response. Although these new indicators of muscular dystrophy have increased our general understanding of the molecular pathogenesis of dystrophinopathy, their application as new diagnostic or prognostic biomarkers would require the undesirable usage of invasive methodology. Hence, to reduce the need for diagnostic muscle biopsy procedures, more recent efforts have focused on the proteomic screening of suitable body fluids, such as plasma, serum or urine, for the identification of changed concentration levels of muscle-derived peptides, protein fragments or intact proteins. The occurrence of muscular dystrophy-related protein species in biofluids will be extremely helpful for the future development of cost-effective and non-invasive diagnostic procedures. Novel biomarker signatures of dystrophinopathies will be indispensible for the swift evaluation of innovative therapeutic approaches, such as exon skipping, codon-read-through or stem cell therapy.