The Molecular and Cellular Basis of Hutchinson-Gilford Progeria Syndrome and Potential Treatments

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, autosomal-dominant, and fatal premature aging syndrome. HGPS is most often derived from a de novo point mutation in the LMNA gene, which results in an alternative splicing defect and the generation of the mutant protein, progerin. Progerin behaves in a dominant-negative fashion, leading to a variety of cellular and molecular changes, including nuclear abnormalities, defective DNA damage response (DDR) and DNA repair, and accelerated telomere attrition. Intriguingly, many of the manifestations of the HGPS cells are shared with normal aging cells. However, at a clinical level, HGPS does not fully match normal aging because of the accelerated nature of the phenotypes and its primary effects on connective tissues. Furthermore, the epigenetic changes in HGPS patients are of great interest and may play a crucial role in the pathogenesis of HGPS. Finally, various treatments for the HGPS patients have been developed in recent years with important effects at a cellular level, which translate to symptomatic improvement and increased lifespan.

Keywords: HGPS; Hutchinson–Gilford progeria syndrome; aging; laminopathy; progeria.

Figure 1

The structure of the human LMNA gene. Lamin C is encoded by exons 1 to 10, while lamin A is encoded by exons 1 to 12. Various mutations identified correlate to pathologies that cause progeroid syndromes and/or segmental diseases affecting connective tissues. EDMD, Emery–Dreifuss muscular dystrophy. APS, atypical progeroid syndromes. HGPS, Hutchinson–Gilford progeria syndrome. AWS, atypical Werner syndrome. FPLD, Dunnigan familial partial lipodystrophy. MAD, mandibuloacral dysplasia.

Figure 2

The differences between processing/modifying a normal prelamin A protein and the progerin mutant. (A): Normal splicing generates a prelamin A protein, which has a terminal CaaX box. The “C” denotes cysteine, “a” is an aliphatic residue, and “X” is any amino acid. The cysteine residue is initially prenylated by a 15-carbon isoprenoid unit. Subsequently, the aaX motif is cleaved by ZMPSTE24, and then a carboxyl-methyl group is added by isoprenylcysteine carboxyl-methyltransferase (ICMT). The final cleavage step is performed by ZMPSTE24, removing 15 amino acids from the C-terminal region including the farnesylated cysteine. (B): 1824 (C>T) mutation at the human LMNA gene generates a cryptic donor splice site. The cryptic donor splice site is improperly recognized by the spliceosome, leading to a 50 amino acid (a.a.) deletion in the prelamin A protein including the ZMPSTE24 cleavage site (pink rectangle). The next few steps mirror normal lamin A production. The final ZMPSTE24-mediated step does not occur due to absence of the ZMPSTE24 cleavage site, resulting in a permanently farnesylated and carboxyl-methylated molecule.

Figure 3

Nuclear structure, nuclear membrane protein, and chromatin alterations with the expression of progerin. (A): Emerin and SUN1 are inner nuclear membrane proteins that interact with lamin A. (B): LAP2α is a protein localized to the nucleoplasm also in association with lamin A. Furthermore, they both play an important role in regulating the phosphorylated retinoblastoma (Rb) protein (pRb) and E2F1 (a transcription factor). (C): After the expression of progerin, chromatin alterations are identified with the typical heterochromatin localizing inside the nucleoplasm. In addition, there are nuclear shape aberrations as well as decreased LAP2α expression. (D): Increased SUN1 and emerin expression correlated with progerin presence at the nuclear membrane.

Figure 4

Aberrant DNA damage response (DDR) and telomere positioning in progerin-positive cells. (A): Initial and downstream DDR signaling perturbed in HGPS cells. (B): Decreased mobility of telomeres identified, with more than half in proximity of the nuclear lamina. DDR and p53 activation is up-regulated at telomeres. p53 is responsible for much of the senescent phenotype of HGPS cells, and its activation is abrogated by the expression of hTERT.