Explore the vast range of titles available.

Hutchinson–Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A‐type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped promyelocytic nuclear bodies, identified as novel biomarkers in late passage HGPS cell lines. We found that the proteasome inhibitor MG132 induces progerin degradation through macroautophagy and strongly reduces progerin production through downregulation of SRSF‐1 and SRSF‐5 accumulation, controlling prelamin A mRNA aberrant splicing. MG132 treatment improves cellular HGPS phenotypes. MG132 injection in skeletal muscle of Lmna G609G/G609G mice locally reduces SRSF‐1 expression and progerin levels. Altogether, we demonstrate progerin reduction based on MG132 dual action and shed light on a promising class of molecules toward a potential therapy for children with HGPS. Synopsis Progerin is a toxic protein that accumulates in the nuclei of Progeria patients' cells, sequestered in abnormal PML‐NBs. The proteasome inhibitor MG132 is shown to degrade progerin by activating autophagy and transcriptional inhibition through SRSF‐1 and SRSF‐5 splicing regulation. Ubiquitinylated progerin is sequestered into abnormal ProMyelocytic Leukemia Nuclear Bodies (PML‐NBs). Progerin reduction is based on MG132 dual action: autophagy activation and splicing regulation. MG132 in vitro treatment rescues most of the biological hallmarks of progeria. MG132 local treatment efficiently reduces progerin levels in vivo , in the Lmna G609G/G609G mouse model. The powerful and dual activities of MG132 make it a promising drug towards a future and safe therapeutic development for Progeria and related Prelamin‐A processing defective diseases. Graphical Abstract Progerin is a toxic protein that accumulates in the nuclei of Progeria patients' cells, sequestered in abnormal PML‐NBs. The proteasome inhibitor MG132 is shown to degrade progerin by activating autophagy and transcriptional inhibition through SRSF‐1 and SRSF‐5 splicing regulation.

The type V intermediate filament lamins are the principal components of the nuclear matrix, including the nuclear lamina. Lamins are divided into A-type and B-type, which are encoded by three genes, LMNA, LMNB1, and LMNB2. The alternative splicing of LMNA produces two major A-type lamins, lamin A and lamin C. Previous studies have suggested that lamins are involved in cancer development and progression. A-type lamins have been proposed as biomarkers for cancer diagnosis, prognosis, and/or follow-up. The aim of the present study was to investigate lamins in cancer cells from metastatic pleural effusions using immunofluorescence, western blotting, and flow cytometry. In a sub-group of lung adenocarcinomas, we found reduced expression of lamin A but not of lamin C. The reduction in lamin A expression was correlated with the loss of epithelial membrane antigen (EMA)/MUC-1, an epithelial marker that is involved in the epithelial to mesenchymal transition (EMT). Finally, the lamin A expression was inversely correlated with the number of metastatic sites and the WHO Performance status, and association of pleural, bone and lung metastatic localizations was more frequent when lamin A expression was reduced. In conclusion, low lamin A but not lamin C expression in pleural metastatic cells could represent a major actor in the development of metastasis, associated with EMT and could account for a pejorative factor correlated with a poor Performance status.

Progeroid syndromes (PS), including Hutchinson-Gilford Progeria Syndrome (HGPS), are premature and accelerated aging diseases, characterized by clinical features mimicking physiological aging. Most classical HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type lamins. This mutation activates a cryptic splice site, leading to the production of a truncated prelamin A, called prelamin A ∆50 or progerin, that accumulates in HGPS cell nuclei and is a hallmark of the disease. Some patients with PS carry other LMNA mutations and are named “HGPS-like” patients. They produce progerin and/or other truncated prelamin A isoforms (∆35 and ∆90). We previously found that MG132, a proteasome inhibitor, induced progerin clearance in classical HGPS through autophagy activation and splicing regulation. Here, we show that MG132 induces aberrant prelamin A clearance and improves cellular phenotypes in HGPS-like patients’ cells other than those previously described in classical HGPS. These results provide preclinical proof of principle for the use of a promising class of molecules toward a potential therapy for children with HGPS-like or classical HGPS.

The ANRS EP45 \"Aging\" study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The data reported focus on mitochondria, organelles known to be involved in cell senescence. 49 HIV-1 infected patients untreated with antiretroviral therapy, together with 49 seronegative age- and sex-matched control subjects and 81 HIV-1 infected and treated patients, were recruited by 3 AIDS centres (Marseille, Montpellier, Nice; France; http://clinicaltrials.gov/, NCT01038999). In more than 88% of treated patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm(3). ROS (reactive oxygen species) production and ΔΨm (inner membrane potential) were measured by flow cytometry in blood lymphocytes and monocytes (functional parameters). Three mitochondrial network quantitative morphological parameters were computed using confocal microscopy and image analysis. Three PBMC mitochondrial proteins (porin and subunits 2 and 4 of cytochrome C oxidase encoded by mtDNA or nuclear DNA, respectively) were analysed by western blotting. Quantitative changes in PBMC mitochondrial proteins were not induced by either HIV-1 infection or ART. Discriminant analysis integrating functional (ROS production and ΔΨm) or morphological (network volume density, fragmentation and branching) parameters revealed HIV-1 infection and ART differential effects according to cell type. First line ART tended to rescue lymphocyte mitochondrial parameters altered by viral infection, but induced slight changes in monocytes. No statistical difference was found between the effects of three ART regimens on mitochondrial parameters. Correlations between functional parameters and viral load confirmed the damaging effects of HIV-1 in lymphocyte mitochondria. In patients considered to be clinically stable, mitochondria exhibited functional and morphological modifications in PBMCs resulting from either direct or indirect effects of HIV-1 infection (lymphocytes), or from first line ART (monocytes). Together with other tissue impairments, these changes may contribute to global aging.

The ANRS EP45 \"Aging\" study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The present report focuses on lamin A processing, a pathway known to be altered in systemic genetic progeroid syndromes. 35 HIV-1 infected patients being treated with first line antiretroviral therapy (ART, mean duration at inclusion: 2.7±1.3 years) containing boosted protease inhibitors (PI/r) (comprising lopinavir/ritonavir in 65% of patients) were recruited together with 49 seronegative age- and sex-matched control subjects (http://clinicaltrials.gov/, NCT01038999). In more than 88% of patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm³. Prelamin A processing in peripheral blood mononuclear cells (PBMCs) from patients and controls was analysed by western blotting at inclusion. PBMCs from patients were also investigated at 12 and 24 months after enrolment in the study. PBMCs from healthy controls were also incubated with boosted lopinavir in culture medium containing various concentrations of proteins (4 to 80 g/L). Lamin A precursor was not observed in cohort patient PBMC regardless of the PI/r used, the dose and the plasma concentration. Prelamin A was detected in PBMC incubated in culture medium containing a low protein concentration (4 g/L) but not in plasma (60-80 g/L) or in medium supplemented with BSA (40 g/L), both of which contain a high protein concentration. Prelamin A processing abnormalities were not observed in PBMCs from patients under the PI/r first line regimen. Therefore, PI/r do not appear to contribute to lamin A-related aging in PBMCs. In cultured PBMCs from healthy donors, prelamin A processing abnormalities were only observed when the protein concentration in the culture medium was low, thus increasing the amount of PI available to enter cells. ClinicalTrials.gov NCT01038999 http://clinicaltrials.gov/ct2/show/NCT01038999.

Hutchinson-Gilford progeria syndrome (HGPS) is an exceedingly rare but typical progeria, clinical characterized by postnatal growth retardation, midface hypoplasia, micrognathia, premature athersclerosis, absence of subcutaneous fat, alopecia, and generalized osteodysplasia with osteolysis and pathologic fractures. A genomic and transcriptional analysis of LMNA in children affected with HGPS is provided.

Statins and aminobisphosphonates inhibit post-translational modifications and membrane accumulation of progerin, the protein that causes Hutchinson-Gilford progeria syndrome, pointing to a potential combination therapy for this disease. Several human progerias, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by the accumulation at the nuclear envelope of farnesylated forms of truncated prelamin A, a protein that is also altered during normal aging 1 , 2 . Previous studies in cells from individuals with HGPS have shown that farnesyltransferase inhibitors (FTIs) improve nuclear abnormalities associated with prelamin A accumulation, suggesting that these compounds could represent a therapeutic approach for this devastating progeroid syndrome 3 . We show herein that both prelamin A and its truncated form progerin/LAΔ50 undergo alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition, which could explain the low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models. We also show that a combination of statins and aminobisphosphonates efficiently inhibits both farnesylation and geranylgeranylation of progerin and prelamin A and markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid syndromes associated with nuclear-envelope abnormalities.

Recent years have witnessed an exponential growth in the number of identified interactions between biological molecules. These interactions are usually represented as large and complex networks, calling for the development of appropriated tools to exploit the functional information they contain. Random walk with restart is the state-of-the-art guilt-by-association approach. It explores the network vicinity of gene/protein seeds to study their functions, based on the premise that nodes related to similar functions tend to lie close to each others in the networks. In the present study, we extended the random walk with restart algorithm to multiplex and heterogeneous networks. The walk can now explore different layers of physical and functional interactions between genes and proteins, such as protein-protein interactions and co-expression associations. In addition, the walk can also jump to a network containing different sets of edges and nodes, such as phenotype similarities between diseases. We devised a leave-one-out cross-validation strategy to evaluate the algorithms abilities to predict disease-associated genes. We demonstrate the increased performances of the multiplex-heterogeneous random walk with restart as compared to several random walks on monoplex or heterogeneous networks. Overall, our framework is able to leverage the different interaction sources to outperform current approaches. Finally, we applied the algorithm to predict genes candidate for being involved in the Wiedemann-Rautenstrauch syndrome, and to explore the network vicinity of the SHORT syndrome. The source code and the software are freely available at: https://github.com/alberto-valdeolivas/RWR-MH.

We hypothesize that the trisomy 21 (Down syndrome) is the additive and interactive outcome of the triple copy of different regions of HSA21. Because of the small number of patients with partial trisomy 21, we addressed the question in the Mouse in which three chromosomal regions located on MMU10, MMU17 and MMU16 carries almost all the HSA21 homologs. Male mice from four segmental trisomic strains covering the D21S17-ETS2 (syntenic to MMU16) were examined with an exhaustive battery of cognitive tests, motor tasks and MRI and compared with TS65Dn that encompasses D21S17-ETS2. None of the four strains gather all the impairments (measured by the effect size) of TS65Dn strain. The 152F7 strain was close to TS65Dn for motor behavior and reference memory and the three other strains 230E8, 141G6 and 285E6 for working memory. Episodic memory was impaired only in strain 285E6. The hippocampus and cerebellum reduced sizes that were seen in all the strains indicate that trisomy 21 is not only a hippocampus syndrome but that it results from abnormal interactions between the two structures.