Charcot-Marie-Tooth-Disease type 2B1 or CMT2B), lipodystrophies, as well as premature aging syndromes such as Hutchinson Gilford Progeria Syndrome (HGPS), Atypical Werner Syndrome (AWS), and restrictive dermopathy (RD) ( Worman, Fong et al. Lamin-associated diseases or laminopathies encompass a range of phenotypes with different tissue pathologies, including muscular dystrophy disorders (e.g., Emery-Dreyfus Muscular Dystrophy or EDMD), peripheral neuropathies (e.g. The association of mutations in lamin proteins, primarily in the LMNA gene, with over a dozen degenerative disorders underscores the importance of nuclear lamins in health and disease. In addition, lamin expression level is directly linked to mechanical stability of the nucleus, and tissue rigidity and plasticity ( Swift, Ivanovska et al. The current view is that lamins serve a scaffolding role, anchoring chromatin and transcription factors to the nuclear periphery, providing the compartmentalization of the genome that is required for proper DNA transactions such as transcription, replication, and repair, as well as transducing signals from the cytoskeleton into the nucleus. A-type lamins (lamin A/C) result from alternative splicing of the LMNA gene and are found at the nuclear lamina and throughout the nuclear interior, being expressed mainly in differentiated cells. B-type lamins are expressed in all cells and found almost exclusively at the nuclear periphery. The nuclear lamina is composed of the type V intermediate filament proteins A-type lamins (primarily lamin A/C) and B-type lamins (lamin B1/B2), in addition to lamina-associated proteins. The nuclear lamina has emerged as a nuclear compartment with critical roles in the maintenance of nuclear architecture and stability, as well as genome organization and function ( Burke and Stewart 2014, Gruenbaum and Foisner 2015, Gruenbaum and Medalia 2015). Deciphering the molecular mechanisms whereby progerin expression leads to HGPS is an emergent area of research, which could bring us closer to understanding the pathology of aging. Interestingly, progerin is also produced in senescent cells and cells from old individuals, suggesting that progerin accumulation might be a factor in physiological aging. In patients harboring this mutation, a severe premature aging disease develops during childhood. In particular, progerin accumulation elicits nuclear morphological abnormalities, misregulated gene expression, defects in DNA repair, telomere shortening, and genomic instability, all of which limit cellular proliferative capacity. Here, we discuss current views about the molecular mechanisms that contribute to the pathophysiology of this devastating disease, as well as the strategies being tested in vitro and in vivo to counteract progerin toxicity. This review focuses on one of the most severe laminopathies, Hutchinson-Gilford Progeria Syndrome (HGPS), which is caused by aberrant splicing of the LMNA gene and expression of a mutant product called progerin. These diseases include neuropathies, muscular dystrophies, lipodystrophies, and premature aging diseases. In humans, hundreds of mutations in the LMNA gene have been identified and correlated with over a dozen degenerative disorders, referred to as laminopathies. Alterations in lamin A and C that disrupt the integrity of the nuclear lamina affect a whole repertoire of nuclear functions, causing cellular decline. Products of the LMNA gene, primarily lamin A and C, are key components of the nuclear lamina, a proteinaceous meshwork that underlies the inner nuclear membrane and is essential for proper nuclear architecture.
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