Progeria research fund

The aim of the Progeria Research Fund is to provide support for basic scientific research into the causes of premature ageing in Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford Progeria Syndrome, or simply "Progeria" is a genetic disease that affects children. The disease causes premature ageing of the children who usually die in their teens from heart attacks and strokes. At present there is no cure for the disease although in a recent breakthrough, the gene which is at fault in the disease has been identified. Here at Brunel we are involved in critical work understanding how the mutation affects the behaviour of individual cells grown from Progeria donors. We have already shown that these cells are much more fragile than normal cells and that they frequently become damaged and die. Understanding how these cells become damaged and how this leads to their death will provide valuable information needed to develop treatments and even cures for Progeria. In addition, this information will also tell us more about the processes that lead to heart failure and strokes that occurs with old age within the rest of the population. Donations made to the Progeria Research Fund will go directly to support on-going research at Brunel University specifically aimed at understanding the causes of Progeria. The group at Brunel have already made substantial contributions to Progeria research and have extensive collaborations with other laboratories in Europe and America.

The Cause of Hutchinson-Gilford Progeria – A Premature Ageing Syndrome

Scientists working in the Cell and Chromosome Biology Group at Brunel have uncovered the mechanism which results in premature ageing of children suffering from the genetic disease, Hutchinson-Gilford Progeria Syndrome (HGPS). The children have some characteristics similar to those in aged people and have a dramatically foreshortened lifespan. This important piece of work was published in May 2004 in the world-leading journal for ageing research – Experimental Gerontology.

HGPS is a rare genetic disease and until last year the genetic mutation causing this degenerative disease was not known. Surprisingly, the gene that is mutated in these children encodes for a protein that is part of the structure of a cell nucleus called the nuclear lamina. The protein is called lamin A and this finding places HGPS into a family of diseases termed laminopathies. The various laminopathies are caused by different mutations in this same protein. These other diseases include muscular dystrophies, cardiomyopathies, lipodystrophies, nerve, muscle and tendon degeneration, type II diabetes and another premature ageing disease called Werner Syndrome. Some of the symptoms of all these diseases are also associated with natural ageing, suggesting a common link between mutation in this protein and premature ageing.

The scientists at Brunel are a husband and wife team. Dr Ian Kill is an expert on cellular and organismal ageing and Dr Joanna Bridger an expert on nuclear structure and organisation. Both had worked on the protein lamin A previously and so were in an excellent position to pursue this collaborative effort. Cells derived from patients with HGPS were purchased from America and the couple set about deciphering how these cells age in culture and the link between nuclear structure and premature ageing.

When growing the cells in culture they did not behave as expected. To begin with, the cells actively divided very rapidly much faster than cells in normal cultures. Then, towards the end of their life-span many of the cells died through a process known as apoptosis.

graph

The green and yellow lines show the rate of ageing of normal cells. The red and blue lines show the rate of ageing of two HGPS cell lines. Notice how the red and blue lines drop sharply at the end – this is due to cells dying or “apoptosis”

As the cells aged and had divided a number of times it became obvious that the cellular nuclei were damaged and had increasingly peculiar and abnormal shapes.

nuclei

The nucleus in panel A appears normal. The nuclei in panels B to F arise in cultures of HGPS as they get older.

Along with this, lamin A protein was mislocalised from its normal nuclear localisation and an increasing number of cells without any lamin A at all accumulated. Cell death was probably due to the effects of losing lamin A in these cells.

nolamina

nolaminag 

The image above shows staining of DNA in blue and staining for lamin A in green. Normally, lamin A is found at the nuclear rim. However with increasing age of HGPS cells in culture, atypical lamin A staining was seen such as a combination of rim and speckles, speckles only and absence of any lamin A staining. The graph shows the percentage of cells showing the particular pattern of staining in two examples of young and aged HGPS cells.

What then is the link between the behaviour of these cells in culture and premature ageing of children suffering from HGPS? Most normal cells are only able to divide a set number of times and then loose the ability to divide forever but remain alive. Many scientists believe that this process, known as “cellular ageing”, is a major contributory factor in the normal ageing process within the body. The finding that HGPS cells use up their potential for division much faster than normal cells and then die is likely to be at the heart of the process leading to premature ageing in children suffering from HGPS. Certain tissues, such as skin, tendons and blood vessels, continuously replace worn-out or damaged cells. The cells used to replace the worn-out or damaged cells arise through cell division of existing cells. In HGPS this process may be compromised because firstly, cells are dividing too quickly and secondly that the very process of cell division leads to cell loss through apoptosis. Therefore, there would not be sufficient cells to support the normal function of the affected tissues.

The outcome of this research will help in understanding HGPS, how its symptoms can best be treated and will lead to further research aimed at designing a much-needed cure. Furthermore, understanding premature ageing will help us to understand normal ageing and aid in increasing the health-span of aged individuals.

Dr Ian Kill teaches Cell Biology and Dr Joanna Bridger teaches Developmental Biology in the Centre for Cell and Chromosome Biology, Division of Biosciences at Brunel University. Both head active Research Laboratories.

Page last updated: Tuesday 05 November 2013