Molecular insights into the premature aging disease progeria.

Sandra Vidak,Roland Foisner

doi:10.1007/s00418-016-1411-1

Sandra Vidak, Roland Foisner

Open Access

https://doi.org/10.1007/s00418-016-1411-1

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Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease presenting many features resembling the normal aging process. HGPS patients die before the age of 20 years due to cardiovascular problems and heart failure. HGPS is linked to mutations in the LMNA gene encoding the intermediate filament protein lamin A. Lamin A is a major component of the nuclear lamina, a scaffold structure at the nuclear envelope that defines mechanochemical properties of the nucleus and is involved in chromatin organization and epigenetic regulation. Lamin A is also present in the nuclear interior where it fulfills lamina-independent functions in cell signaling and gene regulation. The most common LMNA mutation linked to HGPS leads to mis-splicing of the LMNA mRNA and produces a mutant lamin A protein called progerin that tightly associates with the inner nuclear membrane and affects the dynamic properties of lamins. Progerin expression impairs many important cellular processes providing insight into potential disease mechanisms. These include changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence. In this review, we discuss these pathways and their potential contribution to the disease pathologies as well as therapeutic approaches used in preclinical and clinical tests.

Highlights

Aging is a universal process in biological organisms that is characterized by a time-dependent progressive decline in cellular and tissue function
A recent study demonstrated that only 30 % of all cellular laminaassociated domains (LADs) in the genome associate with the nuclear envelope in a given cell, while the rest localizes in the nuclear interior, but LADs are stochastically reshuffled to the nuclear lamina in each cell cycle (Kind et al 2013)
Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases

Summary

Introduction

Aging is a universal process in biological organisms that is characterized by a time-dependent progressive decline in cellular and tissue function. One of the first of these mouse models was generated by knocking-in a mutant Lmna allele (LmnaHG) that produces exclusively progerin but no wild-type lamin A and lamin C (Yang et al 2005) This knock-in mouse model displays phenotypes similar to HGPS children including loss of hair (alopecia) and subcutaneous fat, osteoporosis and premature death, but no cardiovascular defects were reported. Zmpste24−/− mice are normal at birth, but within 4–6 weeks of age they start to display many of the progeroid phenotypes such as growth retardation, alopecia, loss of adipose tissue, multiple spontaneous bone fractures, abnormal nuclear morphology and premature death, as well as muscular dystrophy and dilated cardiomyopathy (Bergo et al 2002; Pendas et al 2002) The latter phenotypes may be linked to the fact that no mature lamin A is produced in these mice, while HGPS phenotypes may be caused by the accumulation of farnesylated prelamin A.

Concluding remarks

Findings

Compliance with ethical standards