Progeria: translational insights from cell biology

Abstract

Cell biologists love to think outside the box, pursuing many surprising twists and unexpected turns in their quest to unravel the mysteries of how cells work. But can cell biologists think outside the bench? We are certain that they can, and clearly some already do. To encourage more cell biologists to venture into the realm of translational research on a regular basis, we would like to share a handful of the many lessons that we have learned in our effort to develop experimental treatments for Hutchinson-Gilford progeria syndrome (HGPS), an endeavor that many view as a "poster child" for how basic cell biology can be translated to the clinic.

Figure 1.

Posttranslational processing of lamin A. A farnesyl group is added to the C terminus of the lamin A protein by the enzyme farnesyltransferase, and, subsequently, the last three amino acids are cleaved by the endoprotease ZMPSTE24. ZMPSTE24 then removes the terminal 15 amino acids, a step that is blocked in HGPS because of the internal deletion of the cleavage site in the progerin protein.

Figure 2.

Defects in HGPS cells. (A) Abnormal nuclear morphology (nuclear blebbing). A nucleus of a passage 17 HGPS cell (HGADFN167) was stained in green with an anti–lamin A/C antibody. (B) Mitotic defects. Nuclear disassembly is incomplete at the onset of mitosis. Progerin (green signal) forms giant aggregates in mitotic cytoplasm. DNA is stained in blue. (C) Binucleation. A binucleated HGPS cell (HGADFN167) stained with an anti-progerin antibody is shown in green. (D) Premature senescence. Senescence-associated β-galactosidase staining is shown for HGPS cells (HGADFN167) at passage 17. (E) Loss of peripheral heterochromatin and extensive nuclear disorganization of a passage 18 HGPS cell (HGADFN167). Source of cells: the Progeria Research Foundation Cell and Tissue Bank (Providence, RI). A, D, and E are courtesy of K. Cao. B and C are from Cao et al. (2007), copyright the National Academy of Sciences. Bars: (A–C and E) 5 µm; (D) 20 µm.

Figure 3.

Children with HGPS. Participants in a clinical trial of an FTI. Photographs courtesy of The Progeria Research Foundation.