UNDERSTANDING AND TREATMENT OF HUTCHINSON-GILFORD PROGERIA SYNDROME, A MODEL FOR NORMAL AGING

AbstractHuman aging affects the entire organism, but aging of the brain must undoubtedly be different from that of all other organs, as neurons are highly differentiated postmitotic cells, for the majority of which the lifespan in the postnatal period is equal to the lifespan of the entire organism. In this work, we examine the distinctive features of brain aging and neurogenesis during normal aging, pathological aging (Alzheimer’s disease), and accelerated aging (Hutchinson-Gilford progeria syndrome and Werner syndrome).

Download Full-text

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

Cells ◽

10.3390/cells9020395 ◽

2020 ◽

Vol 9 (2) ◽

pp. 395

Author(s):

Ray Kreienkamp ◽

Susana Gonzalo

Keyword(s):

Aging Process ◽

Therapeutic Potential ◽

Normal Aging ◽

Premature Aging ◽

Metabolic Dysfunction ◽

Epigenetic Changes ◽

Patient Death ◽

New Research ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford Progeria Syndrome (HGPS) is a segmental premature aging disease causing patient death by early teenage years from cardiovascular dysfunction. Although HGPS does not totally recapitulate normal aging, it does harbor many similarities to the normal aging process, with patients also developing cardiovascular disease, alopecia, bone and joint abnormalities, and adipose changes. It is unsurprising, then, that as physicians and scientists have searched for treatments for HGPS, they have targeted many pathways known to be involved in normal aging, including inflammation, DNA damage, epigenetic changes, and stem cell exhaustion. Although less studied at a mechanistic level, severe metabolic problems are observed in HGPS patients. Interestingly, new research in animal models of HGPS has demonstrated impressive lifespan improvements secondary to metabolic interventions. As such, further understanding metabolism, its contribution to HGPS, and its therapeutic potential has far-reaching ramifications for this disease still lacking a robust treatment strategy.

Download Full-text

Premature arterial stiffening in Hutchinson-Gilford Progeria Syndrome linked to early induction of Lysyl Oxidase (LOX) and corrected by LOX inhibition

10.1101/773184 ◽

2019 ◽

Author(s):

Ryan von Kleeck ◽

Sonja A. Brankovic ◽

Ian Roberts ◽

Elizabeth A. Hawthorne ◽

Kyle Bruun ◽

...

Keyword(s):

Cross Sections ◽

Carotid Arteries ◽

Lysyl Oxidase ◽

Normal Aging ◽

Premature Aging ◽

Arterial Mechanics ◽

Arterial Stiffening ◽

Ecm Remodeling ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

SUMMARYArterial stiffening is a hallmark of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the key molecular regulators initiating arterial stiffening in HGPS remain unknown. To identify these early events, we compared arterial mechanics and ECM remodeling in very young HGPS (LMNAG609G/G609G) mice to those of age-matched and much older wild-type (WT) mice. Biaxial inflation-extension tests of carotid arteries of 2-month mice showed that circumferential stiffness of HGPS arteries was comparable to that of 24-month WT controls whereas axial arterial stiffening, an additional hallmark of normal aging, was mostly spared in HGPS. In an effort to identify underlying mechanisms, we examined expression levels of the major stiffness-regulatory molecules in WT and HGPS arteries. Transmission electron microscopy revealed slightly increased amounts of collagen within the elastin folds of HGPS carotid arteries, but this change was barely detectable by immunostaining carotid cross sections or qPCR of isolated aortas for collagens I, III, or V. Elastin integrity was also similar in the WT and HGPS arteries. In contrast, immunostaining readily revealed an increased expression of Lysyl oxidase (LOX) protein in young HGPS carotid arteries relative to aged-matched WT controls. Further analysis showed that HGPS arteries express increased amounts of LOX mRNA, and this effect extends to each of the arterial LOX family members. Remarkably, treatment of HGPS mice with the pan-LOX inhibitor β-aminopropionitrile (BAPN) restored near-normal circumferential arterial mechanics to HGPS carotid arteries, mechanistically and causally linking LOX upregulation to premature arterial stiffening in HGPS. Finally, we show that this premature increase in arterial LOX expression in HGPS foreshadows the increased expression of LOX that accompanies circumferential arterial stiffening during normal aging.

Download Full-text

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

Download Full-text

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

Download Full-text

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

Download Full-text

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.

Download Full-text

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.

Download Full-text