Self-organization of cellular structures induced by the overexpression of nuclear envelope proteins: a correlative light and electron microscopy study.

The mechanisms by which the supramolecular order is formed inside the cell nucleus remain poorly understood. So far, two major hypotheses - ordered assembly and stochastic self-organization - have been discussed. To determine which mechanism is responsible for the formation of nuclear envelope, cells overexpressing one of the nuclear envelope proteins (lamin A, lamin B1, pom121 or ndc1) were investigated. According to the ordered assembly model, the presence of an excessive amount of a component has no effect in the formation of the normal structure of a nuclear envelope because it is programmed and cannot be distorted. In contrast, according to the self-organization concept, there is no such strictly determined cellular structures, and an excessive amount of even one component will affect the cellular organization. In the present study, formation of a redundant nuclear envelope was observed in the case of lamin B1 and lamin A overexpression. In the case of the nucleoporins pom121 and ndc1, no incorporation of the overexpressed proteins into the nuclear envelope was observed on the first day after transfection; however, the remodeling of endoplasmic reticulum elements and the formation of membrane aggregates in the cytoplasm were observed. After mitosis, pom121 from the cytoplasmic aggregates was translocated into the redundant nuclear envelope in which it induced inner nuclear membrane protrusions. Therefore, our results indicate that the formation of the nuclear envelope is not predetermined and that an excessive amount of even one protein component can affect cellular structure formation. This study concluded that nuclear envelope formation is achieved by the self-organization mechanism.

Are There Common Mechanisms Between the Hutchinson-Gilford Progeria Syndrome and Natural Aging?

The Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by mutations of the LMNA gene leading to increased production of a partially processed form of the nuclear fibrillar protein lamin A - progerin. Progerin acts as a dominant factor that leads to multiple morphological anomalies of cell nuclei and disturbances in heterochromatin organization, mitosis, DNA replication and repair, and gene transcription. Progerin-positive cells are present in primary fibroblast cultures obtained from the skin of normal donors at advanced ages. These cells display HGPS-like defects in nuclear morphology, decreased H3K9me3 and HP1, and increased histone H2AX phosphorylation marks of the DNA damage loci. Inhibition of progerin production in cells of aged non-HGPS donors in vivo increases the proliferative activity, H3K9me3, and HP1, and decreases the senescence markers p21, IGFBP3, and GADD45B to the levels of young donor cells. Thus, progerin-dependent mechanisms act in natural aging. Excessive activity of the same mechanisms may well be the cause of premature aging in HGPS. Telomere attrition is widely regarded to be one of the primary hallmarks of aging. Progerin expression in normal human fibroblasts accelerates the loss of telomeres. Changes in lamina organization may directly affect telomere attrition resulting in accelerated replicative senescence and progeroid phenotypes. The chronological aging in normal individuals and the premature aging in HGPS patients are mediated by similar changes in the activity of signaling pathways, including downregulation of DNA repair and chromatin organization, and upregulation of ERK, mTOR, GH-IGF1, MAPK, TGFß, and mitochondrial dysfunction. Multiple epigenetic changes are common to premature aging in HGPS and natural aging. Recent studies showed that epigenetic systems could play an active role as drivers of both forms of aging. It may be suggested that these systems translate the effects of various internal and external factors into universal molecular hallmarks, largely common between natural and accelerated forms of aging. Drugs acting at both natural aging and HGPS are likely to exist. For example, vitamin D3 reduces the progerin production and alleviates most HGPS features, and also slows down epigenetic aging in overweight and obese non-HGPS individuals with suboptimal vitamin D status.