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The expression of Lamin A mutant R321X leads to endoplasmic reticulum stress with aberrant Ca2+ handling.

 

J. Cell Mol Med 2016 Jul 15. doi: 10.1111/jcmm.12926. 

 

Carmosino M, Gerbino A, Schena G, Procino G, Miglionico R, Forleo C, Favale S, Svelto M

 

Mutations in the Lamin A/C gene (LMNA), which encodes A-type nuclear Lamins, represent the most frequent genetic cause of dilated cardiomyopathy (DCM). This study is focused on a LMNA nonsense mutation (R321X) identified in several members of an Italian family that produces a truncated protein isoform, which co-segregates with a severe form of cardiomyopathy with poor prognosis. However, no molecular mechanisms other than nonsense mediated decay of the messenger and possible haploinsufficiency were proposed to explain DCM. Aim of this study was to gain more insights into the disease-causing mechanisms induced by the expression of R321X at cellular level. We detected the expression of R321X by Western blotting from whole lysate of a mutation carrier heart biopsy. When expressed in HEK293 cells, GFP- (or mCherry)-tagged R321X mislocalized in the endoplasmic reticulum (ER) inducing the PERK-CHOP axis of the ER stress response. Of note, confocal microscopy showed phosphorylation of PERK in sections of the mutation carrier heart biopsy. ER mislocalization of mCherry-R321X also induced impaired ER Ca2+ handling, reduced capacitative Ca2+ entry at the plasma membrane and abnormal nuclear Ca2+ dynamics. In addition, expression of R321X by itself increased the apoptosis rate. In conclusion, R321X is the first LMNA mutant identified to date, which mislocalizes into the ER affecting cellular homeostasis mechanisms not strictly related to nuclear functions.

 

 

medline link: www.ncbi.nlm.nih.gov/pubmed/27421120#

 


ASSOCIATION OF RETINOIC ACID AND RAPAMYCIN INVERT THE LAMIN A-TO-PROGERIN RATIO IN HGPS FIBROBLASTS AND NORMALIZE THE PROGERIC PHENOTYPE

All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype. Oncotarget. 2015 Aug 13.

Pellegrini C, Columbaro M, Capanni C, D'Apice MR, Cavallo C, Murdocca M, Lattanzi G, Squarzoni S.

 

The LMNA promoter contains a retinoic acid responsive element, so all-trans retinoic acid administration was tested in cultured HGPS fibroblasts. Rapamycin was associated to further degrade progerin. All-trans retinoic acid reduces progerin and prelamin A by transcriptional downregulation and protein degradation, synergistically with low-dosage rapamycin, and increases the lamin A to progerin ratio. Cell dynamics and cellular proliferation are rescued through recovery of DNA damage response factor PARP1 and chromatin-associated nuclear envelope proteins LAP2? and BAF. The combined all-trans retinoic acid-rapamycin treatment is dramatically efficient, highly reproducible and represents a promising new approach in Hutchinson-Gilford Progeria therapy.

 

medline link: www.ncbi.nlm.nih.gov/pubmed/26359359


A WIDE SCREENING OF APPROVED DRUGS IDENTIFIES RETINOIDS AS POSSIBLE AGENTS CONTRASTING PROGERIA

A high-content imaging-based screening pipeline for the systematic identification of anti-progeroid compounds. Methods. 2015 Sep 1.

Kubben N, Brimacombe KR, Donegan M, Li Z, Misteli T.

 

This study attempts to identify druggable targets with anti-progeroid effects. By means of a high-throughput, high-content imaging based screening method a library of 2816 FDA approved drugs was screened. Retinoids were identified as a novel class of compounds that reverses aging defects in HGPS patient skin fibroblasts.

 

medline link: www.ncbi.nlm.nih.gov/pubmed/26341717


LAP2 ? RESCUES HGPS CELL PROLIFERATION DEFECTS AND LOSS OF H3K27me3

Progerin reduces LAP2?-telomere association in Hutchinson-Gilford progeria.     Elife. 2015 Aug 27;4.

Chojnowski A, Ong PF, Wong ES, Lim JS, Mutalif RA, Navasankari R, Dutta B, Yang H, Liow YY, Sze SK, Boudier T, Wright GD, Colman A, Burke B, StewartCL, Dreesen O.

 

LAP2? (lamina-associated polypeptide-?) interacts with lamin A but to a lesser extent with progerin: super-resolution microscopy revealed impaired LAP2? association with telomeres. Increasing LAP2? levels rescues cell proliferation defects and loss of H3K27me3, whereas lowering LAP2 levels exacerbates progerin-induced defects.

 

medline link: www.ncbi.nlm.nih.gov/pubmed/26312502


SIRT6 IMPEDES HGPS CELLS SENESCENCE

Restoring SIRT6 Expression in Hutchinson-Gilford Progeria Syndrome Cells Impedes Premature Senescence and Formation of Dysmorphic Nuclei.   Pathobiology. 2015 Feb 28;82(1):9-20.

Endisha H, Merrill-Schools J, Zhao M, Bristol M, Wang X, Kubben N, Elmore LW.

 

Typical HGPS fibroblasts exhibit reduced levels of SIRT6 protein via a mechanism that remains to be elucidated. Our findings suggest that restoring SIRT6 expression in HGPS cells may partially impede senescence and the formation of dysmorphic nuclei

 

medline link: www.ncbi.nlm.nih.gov/pubmed/25765721


SULFORAPHANE DEGRADES PROGERIN IN HUTCHINSON-GILFORD PROGERIA FIBROBLASTS

Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts.  Aging Cell. 2015 Feb;14(1):78-91

Gabriel D, Roedl D, Gordon LB, Djabali K.

 

HGPS cultures were treated with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS and has no synergistic effect with FTIs..

 

medline link: www.ncbi.nlm.nih.gov/pubmed/25510262


THE NGPS MUTATED BAF PROTEIN CANNOT BIND DNA CORRECTLY BUT LOCALIZES PROPERLY AT THE NUCLEAR ENVELOPE

Néstor-Guillermo Progeria Syndrome: a biochemical insight into Barrier-to-Autointegration Factor 1, alanine 12 threonine mutation.  BMC Mol Biol. 2014 Dec 12;15:27

Paquet N, Box JK, Ashton NW, Suraweera A, Croft LV, Urquhart AJ, Bolderson E, Zhang SD, O'Byrne KJ, Richard DJ.

 

In the NGPS syndrome, the BANF1 A12T protein is correctly folded and stable. The observed phenotype, due to the disruption of the DNA binding surface of the A12T mutant. It is demonstrated that the BANF1 A12T protein is impaired in binding DNA but not nuclear envelope proteins. The ectopic expression of the mutant protein induces the NGPS cellular phenotype, while the protein localizes normally to the nuclear envelope.

 

medline link: www.ncbi.nlm.nih.gov/pubmed/25495845


ENHANCED WNT/?-CATENIN SIGNALING CONTRIBUTES TO CARDIAC X-EDMD DEFECTS AND PHARMACOLOGICAL INHIBITION OF ?-CATENIN CONTRIBUTES TO THEIR NORMALIZATION

Attenuation of Wnt/?-catenin activity reverses enhanced generation of cardiomyocytes and cardiac defects caused by the loss of emerin.  Hum Mol Genet. 2014 Sep 30

Stubenvoll A, Rice M, Wietelmann A, Wheeler M, Braun T.

 

An increase of cardiomyocytes in emerin-null adult mice is accompanied with decreased numbers of multinucleated cells. Depletion of emerin in mouse ES cell-derived cardiomyocytes by shRNA caused hyperactivation of Wnt/?-catenin signaling, increased proliferation and abrogated timely cardiac differentiation. Emerin-null mice exhibited increased Wnt/?-catenin signaling and cardiac dysfunction. Pharmacological inhibition of ?-catenin normalized proliferation and differentiation of ES cell-derived cardiomyocytes while inactivation of a single allele of ?-catenin rescued cardiac dysfunction in emerin-null mice.

 

 

medline link: www.ncbi.nlm.nih.gov/pubmed/25274778


PROMOTING AUTOPHAGY: A NEW ROLE FOR EMERIN

New role for EMD (emerin), a key inner nuclear membrane protein, as an enhancer of autophagosome formation in the C16-ceramide autophagy pathway

 

Deroyer C, Rénert AF, Merville MP, Fillet M.. Autophagy. 2014 May 7;10(7).

 

 

 

Ceramides are bioactive signaling molecules; C16-ceramide induces EMD phosphorylation, phosphorylated EMD binds MAP1LC3B leading to an increase of autophagosome formation thus enhancing autophagy pathway in colon cancer cells.

 

http://www.ncbi.nlm.nih.gov/pubmed/24819607


 

PROGERIC VASCULAR MUSCLE CELL DEATH IS REGULATED THROUGH PARP1 DOWNREGULATION.

Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1

 

Zhang H, Xiong ZM, Cao K.. Proc Natl Acad Sci U S A. 2014 May 19

 

 

 

Progerin stimulates suppression of PARP1 and triggers an activation of the error-prone nonhomologous end joining response for repairing DNA. As a result, most HGPS SMCs exhibit prolonged mitosis and die of mitotic catastrophe.

 

http://www.ncbi.nlm.nih.gov/pubmed/24843141



ALSO ACROGERIA MAY BE CONSIDERED A LAMINOPATHY.

New Lamin A Mutation Associated with Acrogeria Syndrome.

 

Hadj-Rabia S, Mashiah J, Roll P, Boyer A, Bourgeois P, Van Kien PK, Lévy N, De Sandre-Giovannoli A, Bodemer C, Navarro C. J Invest Dermatol. 2014 Mar 31. in press

 

 

 

Acrogeria is a form of skin atrophy with premature aging aspects. It has heterogeneous origin, reportedly many cases being caused by collagen III mutations. A patient is now described bearing a form caused by a  LMNA C591S mutation.

 

http://www.ncbi.nlm.nih.gov/pubmed/24687084


 

ALTERATIONS IN THE CNS WHITE MATTER MAY COEXIST WITH MUSCULAR DYSTROPHY FORMS.

Congenital muscular dystrophy with dropped head phenotype and cognitive impairment due to a novel mutation in the LMNA gene.

 

Bonati U, Bechtel N, Heinimann K, Rutz E, Schneider J, Frank S, Weber P, Fischer D. Neuromuscul Disord. 2014 Feb 15. in press.

 

A patient is described who shows cognitive impairment associated with muscular symptoms. In analogous congenital muscular dystrophy cases, a screening is proposed to exclude white matter lesions and cognitive impairment..

  

http://www.ncbi.nlm.nih.gov/pubmed/24684859

 


 

CENTENARIAN LAMINS: RAPAMYCIN TARGETS IN LONGEVITY.

Lamins are rapamycin targets that impact human longevity: a study in centenarians.

 

Lattanzi G, Ortolani M, Columbaro M, Prencipe S, Mattioli E, Lanzarini C, Maraldi NM, Cenni V, Garagnani P, Salvioli S, Storci G, Bonafè M, Capanni C, Franceschi C. J Cell Sci. 2014 Jan 1;127(Pt 1):147-57.

 

Prelamin A accumulates in cells of centenarian people due to decreased activity of the enzyme ZMPSTE24. This causes heterochromatin reduction and increase of P53BP1, effects which may be reproduced in “young nuclei”  by rapamycin treatment, suggesting that both Prelamin A and P53BP1 area targets for this drug.

 

medline link http://www.ncbi.nlm.nih.gov/pubmed/24155329

 

 

 

 

 

 

 

 


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