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- Fong, L. G., et al.
(författare)
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Prelamin A and lamin A appear to be dispensable in the nuclear lamina
- 2006
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Ingår i: J Clin Invest. ; 116:3, s. 743-752
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Tidskriftsartikel (refereegranskat)abstract
- Lamin A and lamin C, both products of Lmna, are key components of the nuclear lamina. In the mouse, a deficiency in both lamin A and lamin C leads to slow growth, muscle weakness, and death by 6 weeks of age. Fibroblasts deficient in lamins A and C contain misshapen and structurally weakened nuclei, and emerin is mislocalized away from the nuclear envelope. The physiologic rationale for the existence of the 2 different Lmna products lamin A and lamin C is unclear, although several reports have suggested that lamin A may have particularly important functions, for example in the targeting of emerin and lamin C to the nuclear envelope. Here we report the development of lamin C-only mice (Lmna(LCO/LCO)), which produce lamin C but no lamin A or prelamin A (the precursor to lamin A). Lmna(LCO/LCO) mice were entirely healthy, and Lmna(LCO/LCO) cells displayed normal emerin targeting and exhibited only very minimal alterations in nuclear shape and nuclear deformability. Thus, at least in the mouse, prelamin A and lamin A appear to be dispensable. Nevertheless, an accumulation of farnesyl-prelamin A (as occurs with a deficiency in the prelamin A processing enzyme Zmpste24) caused dramatically misshapen nuclei and progeria-like disease phenotypes. The apparent dispensability of prelamin A suggested that lamin A-related progeroid syndromes might be treated with impunity by reducing prelamin A synthesis. Remarkably, the presence of a single Lmna(LCO) allele eliminated the nuclear shape abnormalities and progeria-like disease phenotypes in Zmpste24-/- mice. Moreover, treating Zmpste24-/- cells with a prelamin A-specific antisense oligonucleotide reduced prelamin A levels and significantly reduced the frequency of misshapen nuclei. These studies suggest a new therapeutic strategy for treating progeria and other lamin A diseases.
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| 4. |
- Yang, S. H., et al.
(författare)
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Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation
- 2005
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Ingår i: Proc Natl Acad Sci U S A. ; 102:29, s. 10291-10296
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Tidskriftsartikel (refereegranskat)abstract
- Hutchinson-Gilford progeria syndrome (HGPS), a progeroid syndrome in children, is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a "CAAX protein" that is farnesylated and then processed further to generate mature lamin A, which is a structural protein of the nuclear lamina. The mutant prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesylation, but the 50-aa deletion prevents the subsequent processing to mature lamin A. The presence of progerin adversely affects the integrity of the nuclear lamina, resulting in misshapen nuclei and nuclear blebs. We hypothesized that interfering with protein farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothesized that the mislocalization of progerin away from the nuclear envelope would improve the nuclear blebbing phenotype. To approach this hypothesis, we created a gene-targeted mouse model of HGPS, generated genetically identical primary mouse embryonic fibroblasts, and we then examined the effect of a farnesyltransferase inhibitor on nuclear blebbing. The farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleoplasm, as determined by immunofluoresence microscopy, and resulted in a striking improvement in nuclear blebbing (P < 0.0001 by chi(2) statistic). These studies suggest a possible treatment strategy for HGPS.
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| 5. |
- Zhang, L, et al.
(författare)
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Blood lipid levels in relation to glucose status in seven populations of Asian origin without a prior history of diabetes : the DECODA study.
- 2009
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Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 25:6, s. 549-557
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dyslipidaemia commonly coexists with diabetes. We investigated the association of lipid profiles with glucose levels in populations of Asian origin without a prior history of diabetes. METHODS: Cross-sectional data of 10,374 men and 12,552 women aged 30-74 years from 14 cohorts, representing seven populations of Asian origin were jointly analysed. Multivariable adjusted linear regression analyses with standardized regression coefficients (beta) were performed to estimate relationships between lipids and plasma glucose. RESULTS: Within each glucose category, fasting plasma glucose (FPG) levels were correlated with increasing levels of triglycerides (TGs), total cholesterol (TC), TC to high-density lipoprotein (HDL) ratio and non-HDL cholesterol (non-HDL-C) (p < 0.05 in most of the ethnic groups) and inversely associated with HDL-C (p < 0.05 in some, but not all, of the populations). The association of lipids with 2-h plasma glucose (2hPG) followed a similar pattern as that for the FPG, except that an inverse relationship between HDL-C and glucose was more commonly observed for 2hPG than for FPG among different ethnic groups. CONCLUSIONS: Hyperglycaemia is associated with adverse lipid profiles in Asians without a prior history of diabetes. The 2hPG appears to be more closely associated with lipid profiles than does FPG. When assessing the risk of cardiovascular disease, the association of the dyslipidaemia with intermediate hyperglycaemia needs to be considered.
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