Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells

Abstract

Ageing is a process that inevitably affects most living organisms and involves the accumulation of macromolecular damage, genomic instability and loss of heterochromatin. Together, these alterations lead to a decline in stem cell function and to a reduced capability to regenerate tissue. In recent years, several genetic pathways and biochemical mechanisms that contribute to physiological ageing have been described, but further research is needed to better characterize this complex biological process. Because premature ageing (progeroid) syndromes, including progeria, mimic many of the characteristics of human ageing, research into these conditions has proven to be very useful not only to identify the underlying causal mechanisms and identify treatments for these pathologies, but also for the study of physiological ageing. In this Review, we summarize the main cellular and animal models used in progeria research, with an emphasis on patient-derived induced pluripotent stem cell models, and define a series of molecular and cellular hallmarks that characterize progeroid syndromes and parallel physiological ageing. Finally, we describe the therapeutic strategies being investigated for the treatment of progeroid syndromes, and their main limitations.

Keywords: Ageing; Progeria; Rejuvenation; iPSCs.

Fig. 1.

Prelamin A physiological and pathological processing and maturation. Processing of prelamin A in (A) normal cells, leading to the generation of mature lamin A and assembly of the normal nuclear envelope, and (B) HGPS cells, where the HGPS-associated mutation (G608G) in the gene encoding prelamin A, LMNA, activates a cryptic splicing site that results in the deletion of 50 amino acids slightly upstream of the C-terminus of prelamin A, encompassing the final cleavage site for ZMPSTE24 and leading to the accumulation of a toxic form of lamin A named progerin. This leads to disruption of the nuclear envelope, detectable as bulging or ‘nuclear blebbing’, which is shown in the representative images of HGPS and NGPS human fibroblasts illustrated below, in comparison to control cells. Lamin A/C (green) and DAPI (blue) staining is shown. Note that nuclear blebbing in NGPS cells is not due to the accumulation of progerin (see main text), and this image has been included purely to demonstrate the phenotype. FTase, farnesyltransferase; ICMT, isoprenylcysteine carboxyl methyltransferase; HGPS, Hutchinson-Gilford progeria syndrome; NGPS, Nestor-Guillermo progeria syndrome; ZMPSTE24, zinc metalloproteinase STE24.

Fig. 2.

Mutations in proteins involved in DNA repair lead to premature ageing syndromes. Diagrams of the proteins involved in (A) double-strand break (DSB) repair, (B) interstrand cross-link (ISL) repair, (C) nucleotide excision repair (NER) and (D) telomere elongation and maintenance, including the shelterin complex, the telomerase complex and the CST (CTC1, STN1 and TEN1) complex (Box 1). Proteins encoded by genes mutated in progeroid syndromes are shown in orange, blue, green and red, whereas non-mutated proteins are shown in grey.

Fig. 3.

The molecular and cellular hallmarks of progeroid syndromes. These nine proposed hallmarks recapitulate the most remarkable features common to different progeroid syndromes and define the mechanisms underlying the pathogenesis of these diseases.