Group Leader: Professor Roger Truscott
In recent years there has been a remarkable transformation in our understanding of human age-related ocular conditions: presbyopia and age-related cataract.
We now know that these result from the gradual deterioration of macromolecules in the lens. Protein breakdown is the major feature and the decomposition products accumulate in the cells of the lens since there is no turnover of protein. Lens proteins are life-long.
Together with collaborators at Wollongong University, we have characterised the products of membrane phospholipid breakdown.
Proteins make up the vast bulk of the lens. Indeed the lens contains the highest concentration of protein of any tissue in the body, so it is perhaps unsurprising that major changes to the proteins give rise to alterations in structure and function of the lens itself. A fundamental question is this: “What are these age-related changes to proteins?”.
Research over the past three years has revealed the major processes responsible for the breakdown of long-lived proteins in the body.
3. Deamidation; and
Surprisingly, all of these changes are the result of breakdown of just three of the 20 amino acids that make up all proteins. These three “weak links” in the amino acid sequence are Aspartic acid, Asparagine and Serine.
Over a period of years there is an inevitable accumulation of degraded proteins. These no longer serve the purpose for which they were synthesised, so their function is compromised and the cells and tissues that contain these damaged proteins also begin to degenerate.
In collaboration with a group at Vanderbilt University, USA, we have now deciphered the mechanism responsible for covalent crosslinking of proteins in cataract lenses. It turns out that breakdown of phosphorylated amino acids (PhosphoSer and PhosphoThr) are responsible and we have elucidated the mechanism of these processes. Thus the ‘last remaining block’ in the cataract puzzle has been characterised.
Two key points arise from this work. Firstly these studies reveal, for the first time, the molecular basis of the major human visual conditions (cataract and presbyopia). Secondly because long-lived proteins are found widely throughout the body, the fundamental information that we discover about protein breakdown in the lens as a function of age, can be transferred to other body tissues. Thus, in an important way, the human lens has become an invaluable model system for understanding age-related diseases in general.
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