Touching Lives - March 2005
Blind from birth
It is a result of recessive mutations in certain genes, which have to be present in both the father and mother and come together by chance, leaving the child without an essential component for their vision.There are currently no treatments for LCA.
The disease happens because the photo receptors, the light sensors in the eye, do not work. These consist of rod and cone cells. Rod cells “see” in black and white, in dim light; cone cells “see” in colour, in bright light.When LCA attacks, neither type of cell works. As LCA acts so early in life, it is important to know for any sort of treatment whether these cells never develop properly, whether they are present but not working, or whether they start out properly but deteriorate very rapidly. Several genes have been identified as being at work in the processes of the disease, with more still to be pinned down.
For the moment Dr Mike Cheetham is working on one gene that causes LCA, known as AIPL1. ^”Unlike some of the other genes that cause LCA, we don’t know exactly what this AIPL1 protein does.^ But we know that it causes a severe form of the disease when it’s mutated, so it’s important to understand what it does in the eye,” says Dr Cheetham.
The gene makes a protein which consists of 384 amino-acid building blocks, and the mutations found in patients lead to the protein not working.
Although we don’t know exactly what AIPL1 does, we can tell from its similarity to other proteins that it is likely to act as a “molecular chaperone”. Like their human equivalents, molecular chaperones prevent the proteins in their charge from misbehaving. They escort them round the body and if the proteins start to malfunction they dispose of them in the body’s “rubbish bin”. Dr Cheetham aims to track which proteins AIPL1 escorts, and what happens when things go wrong in LCA.
Yet there are mysteries involved. Quite clearly the rod and cone cells are both affected in LCA patients, and the protein is present in both kinds of cell while the eye develops. However, it appears only to be in the rod cells of adults. Dr Cheetham thinks that somehow in the later stages of pregnancy or in early childhood, the cone cells “switch off “AIPL1. This suggests that the cone cells no longer need the protein in adulthood, and the protein’s role is different in babies from its role in adults. Finding out what these different roles are will be critical to understanding LCA, and developing treatments.
One of the ways to find out what a protein does is to know the company it keeps — the proteins with which it interacts. Some sophisticated molecular biology techniques can be used to find protein interaction partners. Dr Cheetham will use one involving attaching AIPL1 to half of an essential yeast enzyme. The other half of this enzyme is attached to the many possible proteins made by the eye as it develops. Only when an interaction occurs between AIPL1 and one of its partners can the two halves of the yeast enzyme join up again, and the yeast grow. When we see the yeast growing, we know the proteins have interacted.
Six million samples
This can be a long, exhaustive process of combination and elimination. Dr Cheetham reckons that to cover all the possibilities he could need to screen up to six million samples. Once the potential new interacting partners have been identified, they need to be verified by other techniques, then studied in the eye over the period of development. They may also cause LCA in other cases where the gene mutation hasn’t yet been identified. Dr Cheetham and his colleague Dr van der Spuy have three years to work through some of these problems, and work out what AIPL1 does in the developing eye.
Dr Cheetham believes that the research could have important implications for the understanding of other currently untreatable blinding diseases. Knowing more about the role of molecular chaperones could also have spin-offs in the understanding of how other diseases develop, especially degenerative diseases like Alzheimer’s, where there are accumulations of faulty proteins.
This team has received a Touching Tiny Lives grant worth over £125,000 and is based at University College London.