Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling
Lamins are intermediate filament proteins that assemble into a meshwork underneath the inner nuclear membrane, the nuclear lamina. Mutations in the LMNA gene, encoding lamins A and C, cause a variety of diseases collectively called laminopathies. The disease mechanism for these diverse conditions is not well understood. Since lamins A and C are fundamental determinants of nuclear structure and stability, we tested whether defects in nuclear mechanics could contribute to the disease development, especially in laminopathies affecting mechanically stressed tissue such as muscle. Using skin fibroblasts from laminopathy patients and lamin A/C-deficient mouse embryonic fibroblasts stably expressing a broad panel of laminopathic lamin A mutations, we found that several mutations associated with muscular dystrophy and dilated cardiomyopathy resulted in more deformable nuclei; in contrast, lamin mutants responsible for diseases without muscular phenotypes did not alter nuclear deformability. We confirmed our results in intact muscle tissue, demonstrating that nuclei of transgenic Drosophila melanogaster muscle expressing myopathic lamin mutations deformed more under applied strain than controls. In vivo and in vitro studies indicated that the loss of nuclear stiffness resulted from impaired assembly of mutant lamins into the nuclear lamina. Although only a subset of lamin mutations associated with muscular diseases caused increased nuclear deformability, almost all mutations tested had defects in force transmission between the nucleus and cytoskeleton. In conclusion, our results indicate that although defective nuclear stability may play a role in the development of muscle diseases, other factors, such as impaired nucleo-cytoskeletal coupling, likely contribute to the muscle phenotype.
Monika Zwerger; Diana E. Jaalouk; Maria L. Lombardi; Philipp Isermann; Monika Mauermann; George Dialynas; Harald Herrmann; Lori L. Wallrath; Jan Lammerding
B lymphocytes are often essential to successfully control invading pathogens and play a primary role in the protection afforded by successful vaccines through the production of specific antibodies. However, recent studies have highlighted the complex roles of B cells in infectious diseases, ... more
Over the last decade it has become evident that in addition to producing antibody, B cells activate the immune system by producing cytokines and via antigen presentation. In addition, B cells also exhibit immunosuppressive functions via diverse regulatory mechanisms. This subset of B cells, ... more
Advances in understanding of the immune microenvironment have highlighted the role of immunosuppressive T cell, myeloid, dendritic and monocytic sub-populations in inhibition of the anti-tumor immune response. The role of B cells in modulating the immune response to solid tumors as well as ... more
Despite the decades long battle since the 'war on cancer' was first declared, major breakthroughs toward improving clinical outcomes have remained elusive. Now, with advanced sequencing, scientists have increasingly entered the fray from an evolutionary perspective toward cancer in the hope ... more
Antibiotic resistance has become an increasing public health concern, with MRSA infections and last lines of antibiotic drug treatments having to be increasingly deployed in hospitals and clinics.
In Molecular Biology and Evolution, Oz, et. al., utilized an experimental evolution approach t ... more
The baker's yeast Saccharomyces cerevisiae has been associated with human activities for thousands of years, being the primary biological agent in baking, brewing, winemaking and other fermentation processes. It is also one of the most important model organisms in molecular biology and gene ... more