scholarly journals Small-Molecule Therapeutic Perspectives for the Treatment of Progeria

2021 ◽  
Vol 22 (13) ◽  
pp. 7190
Author(s):  
Jon Macicior ◽  
Beatriz Marcos-Ramiro ◽  
Silvia Ortega-Gutiérrez
Keyword(s):  
Small Molecules ◽  
Nuclear Lamina ◽  
Premature Death ◽  
Therapeutic Strategies ◽  
Mechanisms Of Action ◽  
Lamin A ◽  
Interacting Proteins ◽  
Systemic Disorder ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria.

scholarly journals Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

2016 ◽  
Vol 113 (46) ◽  
pp. E7250-E7259 ◽  
Author(s):  
José Rivera-Torres ◽  
Conrado J. Calvo ◽  
Anna Llach ◽  
Gabriela Guzmán-Martínez ◽  
Ricardo Caballero ◽  
...  
Keyword(s):  
Ventricular Arrhythmia ◽  
Nuclear Lamina ◽  
Premature Death ◽  
Calcium Transient ◽  
Cardiac Repolarization ◽  
Prelamin A ◽  
Calcium Loading ◽  
Junction Protein ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24−/− mouse model of HGPS. Challenge of Zmpste24−/− mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24−/− cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24−/− progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.

scholarly journals Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice

2021 ◽  
Author(s):  
Yuexia Wang ◽  
Khurts Shiladardi ◽  
Trunee Hsu ◽  
Kamsi O. Odinammadu ◽  
Takamitsu Maruyama ◽  
...  
Keyword(s):  
Nuclear Lamina ◽  
Lamin A ◽  
Protein Accumulation ◽  
Loss Of Function ◽  
Prelamin A ◽  
Protein Farnesyltransferase ◽  
Physiological Aging ◽  
Robust Model ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Prelamin A is a farnesylated precursor of lamin A, a nuclear lamina protein. Accumulation of the farnesylated prelamin A variant progerin, with an internal deletion including its processing site, causes Hutchinson-Gilford progeria syndrome. Loss of function mutations in ZMPSTE24, which encodes the prelamin A processing enzyme, lead to accumulation of full-length farnesylated prelamin A and cause related progeroid disorders. Some data suggest that prelamin A also accumulates with physiological aging. Zmpste24-/- mice die young, at ~20 weeks. Because ZMPSTE24 has functions in addition to prelamin A processing, we generated a mouse model to examine effects solely due to the presence of permanently farnesylated prelamin A. These mice have an L648R amino acid substitution in prelamin A that blocks ZMPSTE24-catalyzed processing to lamin A. The LmnaL648R/L648R mice express only prelamin and no mature protein. Notably, nearly all survive to 65-70 weeks, with approximately 40% of male and 75% of female LmnaL648R/L648R having near-normal lifespans of almost 2 years. Starting at ~10 weeks of age, LmnaL648R/L648R mice of both sexes have lower body masses and body fat than controls. By ~20-30 weeks of age, they exhibit detectable cranial, mandibular and dental defects similar to those observed in Zmpste24-/- mice, and have decreased vertebral bone density compared to age- and sex-matched controls. Cultured embryonic fibroblasts from LmnaL648R/L648R mice have aberrant nuclear morphology that is reversible by treatment with a protein farnesyltransferase inhibitor. These novel mice provide a robust model to study the effects of farnesylated prelamin A during physiological aging.

Towards a Drosophila model of Hutchinson–Gilford progeria syndrome

2008 ◽  
Vol 36 (6) ◽  
pp. 1389-1392 ◽  
Author(s):  
Gemma S. Beard ◽  
Joanna M. Bridger ◽  
Ian R. Kill ◽  
David R.P. Tree
Keyword(s):  
Drosophila Melanogaster ◽  
Premature Aging ◽  
Lamin A ◽  
Wild Type ◽  
Drosophila Model ◽  
Numerous Cell ◽  
Cellular Abnormalities ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Adult Drosophila

The laminopathy Hutchinson–Gilford progeria syndrome (HGPS) is caused by the mutant lamin A protein progerin and leads to premature aging of affected children. Despite numerous cell biological and biochemical insights into the basis for the cellular abnormalities seen in HGPS, the mechanism linking progerin to the organismal phenotype is not fully understood. To begin to address the mechanism behind HGPS using Drosophila melanogaster, we have ectopically expressed progerin and lamin A. We found that ectopic progerin and lamin A phenocopy several effects of laminopathies in developing and adult Drosophila, but that progerin causes a stronger phenotype than wild-type lamin A.

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

2010 ◽  
Vol 38 (1) ◽  
pp. 281-286 ◽  
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.

scholarly journals Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome

2006 ◽  
Vol 103 (27) ◽  
pp. 10271-10276 ◽  
Author(s):  
K. N. Dahl ◽  
P. Scaffidi ◽  
M. F. Islam ◽  
A. G. Yodh ◽  
K. L. Wilson ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Nuclear Lamina ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

scholarly journals A pathway linking oxidative stress and the Ran GTPase system in progeria

2014 ◽  
Vol 25 (8) ◽  
pp. 1202-1215 ◽  
Author(s):  
Sutirtha Datta ◽  
Chelsi J. Snow ◽  
Bryce M. Paschal
Keyword(s):  
Oxidative Stress ◽  
Nuclear Membrane ◽  
Nucleocytoplasmic Transport ◽  
Lamin A ◽  
Mutant Form ◽  
Ran Gtpase ◽  
Nuclear Levels ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
The Relationship

Maintaining the Ran GTPase at a proper concentration in the nucleus is important for nucleocytoplasmic transport. Previously we found that nuclear levels of Ran are reduced in cells from patients with Hutchinson–Gilford progeria syndrome (HGPS), a disease caused by constitutive attachment of a mutant form of lamin A (termed progerin) to the nuclear membrane. Here we explore the relationship between progerin, the Ran GTPase, and oxidative stress. Stable attachment of progerin to the nuclear membrane disrupts the Ran gradient and results in cytoplasmic localization of Ubc9, a Ran-dependent import cargo. Ran and Ubc9 disruption can be induced reversibly with H2O2. CHO cells preadapted to oxidative stress resist the effects of progerin on Ran and Ubc9. Given that HGPS-patient fibroblasts display elevated ROS, these data suggest that progerin inhibits nuclear transport via oxidative stress. A drug that inhibits pre–lamin A cleavage mimics the effects of progerin by disrupting the Ran gradient, but the effects on Ran are observed before a substantial ROS increase. Moreover, reducing the nuclear concentration of Ran is sufficient to induce ROS irrespective of progerin. We speculate that oxidative stress caused by progerin may occur upstream or downstream of Ran, depending on the cell type and physiological setting.

scholarly journals Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

2008 ◽  
Vol 19 (12) ◽  
pp. 5238-5248 ◽  
Author(s):  
Brian A. Kudlow ◽  
Monique N. Stanfel ◽  
Christopher R. Burtner ◽  
Elijah D. Johnston ◽  
Brian K. Kennedy
Keyword(s):  
Human Fibroblasts ◽  
Rapid Onset ◽  
Lamin A ◽  
Premature Senescence ◽  
Inhibition Of Proliferation ◽  
Nuclear Lamins ◽  
Cell Immortalization ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Telomere Structure

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, debilitating disease with early mortality and rapid onset of aging-associated pathologies. It is linked to mutations in LMNA, which encodes A-type nuclear lamins. The most frequent HGPS-associated LMNA mutation results in a protein, termed progerin, with an internal 50 amino acid deletion and, unlike normal A-type lamins, stable farnesylation. The cellular consequences of progerin expression underlying the HGPS phenotype remain poorly understood. Here, we stably expressed lamin A mutants, including progerin, in otherwise identical primary human fibroblasts to compare the effects of different mutants on nuclear morphology and cell proliferation. We find that expression of progerin leads to inhibition of proliferation in a high percentage of cells and slightly premature senescence in the population. Expression of a stably farnesylated mutant of lamin A phenocopied the immediate proliferative defects but did not result in premature senescence. Either p53 inhibition or, more surprisingly, expression of the catalytic subunit of telomerase (hTERT) suppressed the early proliferative defects associated with progerin expression. These findings lead us to propose that progerin may interfere with telomere structure or metabolism in a manner suppressible by increased telomerase levels and possibly link mechanisms leading to progeroid phenotypes to those of cell immortalization.

Sign in / Sign up

Export Citation Format

Share Document