Progeria, the nucleolus and farnesyltransferase inhibitors

HGPS (Hutchinson–Gilford progeria syndrome) is a rare genetic disease affecting children causing them to age and die prematurely. The disease is typically due to a point mutation in the coding sequence for the nuclear intermediate-type filament protein lamin A and gives rise to a dominant-negative splice variant named progerin. Accumulation of progerin within nuclei causes disruption to nuclear structure, causes and premature replicative senescence and increases apoptosis. Now it appears that accumulation of progerin may have more widespread effects than previously thought since the demonstration that the presence and distribution of some nucleolar proteins are also adversely affected in progeria cells. One of the major breakthroughs both in the lamin field and for this syndrome is that many of the cellular defects observed in HGPS patient cells and model systems can be restored after treatment with a class of compounds known as FTIs (farnesyltransferase inhibitors). Indeed, it is demonstrated that FTI-277 is able to completely restore nucleolar antigen localization in treated progeria cells. This is encouraging news for the HGPS patients who are currently undergoing clinical trials with FTI treatment.

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Lamin A-linked progerias: is farnesylation the be all and end all?

Biochemical Society Transactions ◽

10.1042/bst0380281 ◽

2010 ◽

Vol 38 (1) ◽

pp. 281-286 ◽

Cited By ~ 7

Author(s):

Dawn T. Smallwood ◽

Sue Shackleton

Keyword(s):

Clinical Trials ◽

Aging Process ◽

Gene Mutations ◽

Accelerated Aging ◽

Membrane Dynamics ◽

Lamin A ◽

Farnesyltransferase Inhibitors ◽

C Terminus ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

HGPS (Hutchinson–Gilford progeria syndrome) is a severe childhood disorder that appears to mimic an accelerated aging process. The disease is most commonly caused by gene mutations that disrupt the normal post-translational processing of lamin A, a structural component of the nuclear envelope. Impaired processing results in aberrant retention of a farnesyl group at the C-terminus of lamin A, leading to altered membrane dynamics. It has been widely proposed that persistence of the farnesyl moiety is the major factor responsible for the disease, prompting clinical trials of farnesyltransferase inhibitors to prevent lamin A farnesylation in children afflicted with HGPS. Although there is evidence implicating farnesylation in causing some of the cellular defects of HGPS, results of several recent studies suggest that aberrant lamin A farnesylation is not the only determinant of the disease. These findings have important implications for the design of treatments for this devastating disease.

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Hutchinson–Gilford Progeria Syndrome (Hgps) And Application Of Gene Therapy Based Crispr/Cas Technology As A Promising Innovative Treatment Approach

Recent Patents on Biotechnology ◽

10.2174/1872208315666210928114720 ◽

2021 ◽

Vol 15 ◽

Author(s):

Mekha Rajeev ◽

Chameli Ratan ◽

Karthik Krishnan ◽

Meenu Vijayan

Keyword(s):

De Novo ◽

Treatment Approach ◽

Genetic Disorder ◽

Symptomatic Relief ◽

Dominant Negative ◽

Premature Aging ◽

Lamin A ◽

Promising Therapeutic Approach ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Background: Hutchinson–Gilford progeria syndrome (HGPS) also known as progeria of childhood or progeria is a rare, rapid, autosomal dominant genetic disorder characterized by premature aging which occurs shortly after birth. HGPS occurs as a result of de novo point mutation in the gene recognized as LMNA gene that encodes two proteins Lamin A protein and Lamin C protein which are the structural components of the nuclear envelope. Mutations in the gene trigger abnormal splicing and induce internal deletion of 50 amino acids leading to the development of a truncated form of Lamin A protein known as Progerin. Progerin generation can be considered as the crucial step in HGPS since the protein is highly toxic to human cells, permanently farnesylated, and exhibits variation in several biochemical and structural properties within the individual. HGPS also produces complications such as skin alterations, growth failure, atherosclerosis, hair and fat loss, and bone and joint diseases. We have also revised all relevant patents relating to Hutchinson-gilford progeria syndrome and its therapy in the current article. Method: The goal of the present review article is to provide information about Hutchinson–Gilford progeria syndrome (HGPS) and the use of CRISPR/Cas technology as a promising treatment approach in the treatment of the disease. The review also discusses about different pharmacological and non-pharmacological methods of treatment currently used for HGPS. Results : The main limitation associated with progeria is the lack of a definitive cure. The existing treatment modality provides only symptomatic relief. Therefore, it is high time to develop a therapeutic method that hastens premature aging in such patients. Conclusion: CRISPR/Cas technology is a novel gene-editing tool that allows genome editing at specific loci, and is found to be a promising therapeutic approach for the treatment of genetic disorders such as HGPS where dominant-negative mutations take place.

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Nuclear Pore Complexes Cluster in Dysmorphic Nuclei of Normal and Progeria Cells during Replicative Senescence

Cells ◽

10.3390/cells10010153 ◽

2021 ◽

Vol 10 (1) ◽

pp. 153

Author(s):

Jennifer M. Röhrl ◽

Rouven Arnold ◽

Karima Djabali

Keyword(s):

Replicative Senescence ◽

Similar Rate ◽

Premature Aging ◽

Nuclear Pore ◽

Nuclear Pore Complexes ◽

Truncated Protein ◽

Exon 11 ◽

Pore Complexes ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease caused by a mutation in LMNA. A G608G mutation in exon 11 of LMNA is responsible for most HGPS cases, generating a truncated protein called “progerin”. Progerin is permanently farnesylated and accumulates in HGPS cells, causing multiple cellular defects such as nuclear dysmorphism, a thickened lamina, loss of heterochromatin, premature senescence, and clustering of Nuclear Pore Complexes (NPC). To identify the mechanism of NPC clustering in HGPS cells, we evaluated post-mitotic NPC assembly in control and HGPS cells and found no defects. Next, we examined the occurrence of NPC clustering in control and HGPS cells during replicative senescence. We reported that NPC clustering occurs solely in the dysmorphic nuclei of control and HGPS cells. Hence, NPC clustering occurred at a higher frequency in HGPS cells compared to control cells at early passages; however, in late cultures with similar senescence index, NPCs clustering occurred at a similar rate in both control and HGPS. Our results show that progerin does not disrupt post-mitotic reassembly of NPCs. However, NPCs frequently cluster in dysmorphic nuclei with a high progerin content. Additionally, nuclear envelope defects that arise during replicative senescence cause NPC clustering in senescent cells with dysmorphic nuclei.

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Faculty Opinions recommendation of Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1013669.191606 ◽

2003 ◽

Author(s):

Anne Bowcock

Keyword(s):

De Novo ◽

Point Mutations ◽

Lamin A ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

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Faculty Opinions recommendation of A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1086874.539808 ◽

2007 ◽

Author(s):

Yosef Gruenbaum

Keyword(s):

Lamin A ◽

Normal Cells ◽

Protein Isoform ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

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Faculty Opinions recommendation of Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1097392.553443 ◽

2007 ◽

Author(s):

Channing Der

Keyword(s):

Farnesyltransferase Inhibitor ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

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High-Throughput Screen Detects Calcium Signaling Dysfunction in Hutchinson-Gilford Progeria Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms22147327 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7327

Author(s):

Juan A. Fafián-Labora ◽

Miriam Morente-López ◽

Fco. Javier de Toro ◽

María C. Arufe

Keyword(s):

Calcium Signaling ◽

Rare Disease ◽

Cell Lines ◽

Healthy Aging ◽

Accelerated Aging ◽

Cytosolic Calcium ◽

Calcium Handling ◽

Therapeutic Window ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a deadly childhood disorder, which is considered a very rare disease. It is caused by an autosomal dominant mutation on the LMNA gene, and it is characterized by accelerated aging. Human cell lines from HGPS patients and healthy parental controls were studied in parallel using next-generation sequencing (NGS) to unravel new non-previously altered molecular pathways. Nine hundred and eleven transcripts were differentially expressed when comparing healthy versus HGPS cell lines from a total of 21,872 transcripts; ITPR1, ITPR3, CACNA2D1, and CAMK2N1 stood out among them due to their links with calcium signaling, and these were validated by Western blot analysis. It was observed that the basal concentration of intracellular Ca2+ was statistically higher in HGPS cell lines compared to healthy ones. The relationship between genes involved in Ca2+ signaling and mitochondria-associated membranes (MAM) was demonstrated through cytosolic calcium handling by means of an automated fluorescent plate reading system (FlexStation 3, Molecular Devices), and apoptosis and mitochondrial ROS production were examined by means of flow cytometry analysis. Altogether, our data suggest that the Ca2+ signaling pathway is altered in HGPS at least in part due to the overproduction of reactive oxygen species (ROS). Our results unravel a new therapeutic window for the treatment of this rare disease and open new strategies to study pathologies involving both accelerated and healthy aging.

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Modelling Nuclear Morphology and Shape Transformation: A Review

Membranes ◽

10.3390/membranes11070540 ◽

2021 ◽

Vol 11 (7) ◽

pp. 540

Author(s):

Chao Fang ◽

Jiaxing Yao ◽

Xingyu Xia ◽

Yuan Lin

Keyword(s):

Shape Change ◽

Boundary Integral ◽

Shape Transformation ◽

Cellular Processes ◽

Physical Mechanisms ◽

Intracellular Forces ◽

Cellular Compartments ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome ◽

Made In

As one of the most important cellular compartments, the nucleus contains genetic materials and separates them from the cytoplasm with the nuclear envelope (NE), a thin membrane that is susceptible to deformations caused by intracellular forces. Interestingly, accumulating evidence has also indicated that the morphology change of NE is tightly related to nuclear mechanotransduction and the pathogenesis of diseases such as cancer and Hutchinson–Gilford Progeria Syndrome. Theoretically, with the help of well-designed experiments, significant progress has been made in understanding the physical mechanisms behind nuclear shape transformation in different cellular processes as well as its biological implications. Here, we review different continuum-level (i.e., energy minimization, boundary integral and finite element-based) approaches that have been developed to predict the morphology and shape change of the cell nucleus. Essential gradients, relative advantages and limitations of each model will be discussed in detail, with the hope of sparking a greater research interest in this important topic in the future.

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