Human Model of Rare Genetic Disease Reveals New Clues To Aging Process

Scientists from A*STAR’s Institute of Medical Biology (IMB) in Singapore and the University of Hong Kong’s Department of Medicine have produced the world’s first human cell model of progeria, a disease resulting in severe premature aging in one in four to eight million children worldwide. This model has allowed them to make new discoveries concerning the mechanism by which progeria works. Their findings were published this month in the prestigious scientific journal, Cell Stem Cell.

Hutchinson-Gilford Progeria Syndrome, also known as progeria, is caused by a mutation in the gene encoding for the protein lamin A, an important component of the membrane surrounding a cell’s nucleus. The mutation results in a truncated form of lamin A called progerin, which in turn causes misshapen cell nuclei and DNA damage. Children with progeria suffer symptoms of premature ageing, including growth retardation, baldness, and atherosclerosis (hardened arteries), and all die in their early teens from either heart attack or stroke.

Led by IMB’s Profs Alan Colman and Colin Stewart, the team used a novel technique of deriving induced pluripotent stem (iPS) cells from cells of human progeria patients. This human progeria model allows the group to trace and analyse the distinctive characteristics of progeria as it progresses in human cells. Previously, only mouse models of the disease were available.

Said Prof Colman, “While mouse models of progeria have been informative, no one mouse model recapitulates all the symptoms seen in humans. Our human progeria model allows us to examine the pathology of the disease at a much closer resolution than previously possible.”

The researchers used their iPS cells to identify two types of cells – mesenchymal stem cells (MSCs) and vascular smooth muscle cells (VSMCs) – that were particularly adversely affected by progeria. This means that a young patient with progeria would typically have fewer MSCs and VSMCs than other children. MSCs were found to be very sensitive to a low oxygen environment and their losses could delay renewal of the various tissues they gave rise to, thus exacerbating the patient’s symptoms of ageing. The same effect on VSMCs could explain why their number was reduced in the patient’s heart vessels.

The group’s findings are a significant boost to existing research on over 10 diseases associated with lamin gene mutations. Prof Stewart previously led a study in mice at IMB showing that progeria affected the connective tissues, potentially via defects in a signaling pathway connecting the nuclear lamina with the extracellular matrix and which was associated with death of the smooth muscle in major blood vessels.

Said Prof Stewart, “This new study provides further evidence for the role of lamin processing in connective tissue function, as well as insights into the normal ageing process. We hope to soon find new routes of intervention to treat this incurable disease. Such interventions may be of use in treating atherosclerosis in general, a condition afflicting many millions of individuals.”

Onset of Genetic Diseases Identified

BARCELONA – Scientists from Universitat Autonoma de Barcelona (UAB) have identified a mechanism that could trigger onset of various genetic diseases.

They have found a process by which proteins with a tendency to cause conformational diseases such as amyotrophic lateral sclerosis, familial amyloidotic polyneuropathy, familial amyloidotic cardiomyopathy, etc. finally end up causing them.

The answer can be found in the separation of the proteins.

According to the researchers Salvador Ventura and Virgmnia Castillo, every day cells produce thousands of new proteins, which renew themselves every second and which, by obeying the orders prescribed in our genetic code, work towards the proper functioning of our body.

However, these proteins occasionally suffer genetic mutations, which can cause changes in their composition, thus preventing them from carrying out their functions and the activities they are assigned.

In many cases this gives way to the formation of toxic macromolecular aggregates – amyloid fibrils – which block our body’s protein quality control system and finally provoke cell death.

Protein aggregation and the misfolding of proteins can be linked to the origin of many conformational diseases, which can be either genetic or spontaneous.

As possible strategies to prevent the dissociation of proteins, the authors propose introducing genetic mutations into the proteins to strengthen their association and developing specific molecules to block the risk regions of already dissociated proteins.

The study appears in journal PLoS Computational Biology.