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.

scholarly journals Imbalanced nucleocytoskeletal connections create common polarity defects in progeria and physiological aging

2019 ◽  
Vol 116 (9) ◽  
pp. 3578-3583 ◽  
Author(s):  
Wakam Chang ◽  
Yuexia Wang ◽  
G. W. Gant Luxton ◽  
Cecilia Östlund ◽  
Howard J. Worman ◽  
...  
Keyword(s):  
Accelerated Aging ◽  
Nuclear Movement ◽  
Prelamin A ◽  
Physiological Aging ◽  
3T3 Fibroblasts ◽  
Normal Individuals ◽  
Actin Cables ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Nih 3T3

Studies of the accelerated aging disorder Hutchinson–Gilford progeria syndrome (HGPS) can potentially reveal cellular defects associated with physiological aging. HGPS results from expression and abnormal nuclear envelope association of a farnesylated, truncated variant of prelamin A called “progerin.” We surveyed the diffusional mobilities of nuclear membrane proteins to identify proximal effects of progerin expression. The mobilities of three proteins—SUN2, nesprin-2G, and emerin—were reduced in fibroblasts from children with HGPS compared with those in normal fibroblasts. These proteins function together in nuclear movement and centrosome orientation in fibroblasts polarizing for migration. Both processes were impaired in fibroblasts from children with HGPS and in NIH 3T3 fibroblasts expressing progerin, but were restored by inhibiting protein farnesylation. Progerin affected both the coupling of the nucleus to actin cables and the oriented flow of the cables necessary for nuclear movement and centrosome orientation. Progerin overexpression increased levels of SUN1, which couples the nucleus to microtubules through nesprin-2G and dynein, and microtubule association with the nucleus. Reducing microtubule-nuclear connections through SUN1 depletion or dynein inhibition rescued the polarity defects. Nuclear movement and centrosome orientation were also defective in fibroblasts from normal individuals over 60 y, and both defects were rescued by reducing the increased level of SUN1 in these cells or inhibiting dynein. Our results identify imbalanced nuclear engagement of the cytoskeleton (microtubules: high; actin filaments: low) as the basis for intrinsic cell polarity defects in HGPS and physiological aging and suggest that rebalancing the connections can ameliorate the defects.

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 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 Activating the synthesis of progerin, the mutant prelamin A in Hutchinson–Gilford progeria syndrome, with antisense oligonucleotides

2009 ◽  
Vol 18 (13) ◽  
pp. 2462-2471 ◽  
Author(s):  
Loren G. Fong ◽  
Timothy A. Vickers ◽  
Emily A. Farber ◽  
Christine Choi ◽  
Ui Jeong Yun ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Prelamin A ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

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.

scholarly journals Physiological and pathological roles of LRRK2 in the nuclear envelope integrity

2019 ◽  
Vol 28 (23) ◽  
pp. 3982-3996 ◽  
Author(s):  
Vered Shani ◽  
Hazem Safory ◽  
Raymonde Szargel ◽  
Ninghan Wang ◽  
Tsipora Cohen ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Cortical Neurons ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Loss Of Function ◽  
Function Mechanism ◽  
Disease Mutations ◽  
Lrrk2 G2019s ◽  
Sporadic Parkinson’S Disease ◽  
Seven In Absentia

Abstract Mutations in LRRK2 cause autosomal dominant and sporadic Parkinson’s disease, but the mechanisms involved in LRRK2 toxicity in PD are yet to be fully understood. We found that LRRK2 translocates to the nucleus by binding to seven in absentia homolog (SIAH-1), and in the nucleus it directly interacts with lamin A/C, independent of its kinase activity. LRRK2 knockdown caused nuclear lamina abnormalities and nuclear disruption. LRRK2 disease mutations mostly abolish the interaction with lamin A/C and, similar to LRRK2 knockdown, cause disorganization of lamin A/C and leakage of nuclear proteins. Dopaminergic neurons of LRRK2 G2019S transgenic and LRRK2 −/− mice display decreased circularity of the nuclear lamina and leakage of the nuclear protein 53BP1 to the cytosol. Dopaminergic nigral and cortical neurons of both LRRK2 G2019S and idiopathic PD patients exhibit abnormalities of the nuclear lamina. Our data indicate that LRRK2 plays an essential role in maintaining nuclear envelope integrity. Disruption of this function by disease mutations suggests a novel phosphorylation-independent loss-of-function mechanism that may synergize with other neurotoxic effects caused by LRRK2 mutations.

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.

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