People who have Hutchinson–Gilford progeria syndrome (HGPS), such as the two-year-old girl pictured, grow old before their time. This distressing condition of premature ageing is a rare but fatal genetic disorder, which is caused by the continuous production of progerin, an abnormal form of the nuclear protein lamin A. But what effects does excess progerin have? Paola Scaffidi and Tom Misteli report that the protein triggers a feature that resembles premature ageing at a cellular level: untimely stem-cell differentiation (P. Scaffidi & T. Misteli Nature Cell Biol. doi:10.1038/ncb1708; 2008).
The authors took a genome-wide approach to identify the genes concerned. They found that, 5 days after production of progerin was increased, the expression of almost 200 genes was dramatically affected, a number that rose to more than 1,000 by day 10. To interpret this striking effect, they searched for cellular pathways in which several progerin-responsive misregulated genes function; this led them to the Notch signalling cascade, which regulates stem-cell differentiation and cell fate. In cells derived from patients with HGPS, the components of Notch signalling were also abnormally active.
The main tissues affected in HGPS are those of mesenchymal origin, including bone, fat and cartilage. The authors looked at the effect of progerin overexpression — and so Notch activation — on normal human mesenchymal stem cells and found that it led to sporadic but spontaneous differentiation of these cells. Next, they triggered differentiation of mesenchymal stem cells into specific lineages in the presence of progerin: increased stem-cell differentiation into the bone lineage was the result. By contrast, progerin seemed to hinder stem cells' transformation into fat cells. These results are consistent with the fact that patients with HGPS have a high turnover of bone but suffer from a loss of subcutaneous fat.
Scaffidi and Misteli's work unravels at least some of the consequences of increased progerin levels associated with premature ageing. But their observations also have implications for understanding the normal process of ageing, as low levels of progerin are present in healthy individuals.
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Shadan, S. Rushed decisions. Nature 452, 39 (2008). https://doi.org/10.1038/452039a