Iron Metabolism and Chelation Program

Lab head: Des Richardson
Location: Blackburn Building (D06), Department of Pathology

Iron is essential for life and growth. While it is well known that iron deficiency can lead to anaemia it is generally not appreciated that iron is critical for the growth of all cells, particularly cancer cells. The Iron Metabolism and Chelation Program is concerned with understanding the basic processes of how tumour cells utilise and transport iron. This knowledge will lead to the development of therapies that can selectively starve tumour cells of iron and inhibit their growth. In addition, we are studying the mechanisms involved in iron loading in the inherited diseases I2-thalassaemia and Friedreich's ataxia.

Lab members: D Richardson (head), C Austin (pfellow), K Dixon (pfellow), P Jansson (pfellow), D Kalinowski (pfellow), D Lane (pfellow), K Loh (pfellow), D Lovejoy (pfellow), P Quach (pfellow), Y Suryo Rahmanto (pfellow), D Zhang (pfellow)

The role of GPI-linked ceruloplasmin in astrocyte iron metabolism

Primary supervisor: Darius Lane

Iron (Fe) is essential for life and is required for the function of many cellular proteins and their prosthetic groups (e.g., haem and Fe-sulfur clusters). The brain has a high requirement for Fe, yet the mechanisms by which Fe enters and is processed by the brain remains a mystery.

Within the brain, astrocytes (‘star-shaped’ glial cells that are at least equivalent in number to neurones) are thought to be important in processing and re-distributing Fe in the brain. Astrocytes extend long processes that ensheathe the brain capillaries and help to form the BBB. Intriguingly, the ends of these processes (i.e., the ‘end-feet’) express a special form of the Fe oxidising enzyme, ceruloplasmin (Cp). This protein is tethered to the external surface of the plasma membrane by a glycophosphatidylinositol (GPI) anchor.

The role of astrocyte GPI-linked Cp is unknown. Possible functions include:

(1)  The oxidation of ferrous iron (Fe2+) to ferric iron (Fe3+) during coupling of Fe to Tf.

(2)  The promotion of astrocytic Fe release by interaction with the Fe exporter, ferroportin.

(3)  Facilitating the uptake of non-Tf-bound Fe by astrocytes.

A variety of fundamental biochemical and molecular biological techniques will be employed in this project, including mammalian cell culture, Western blotting, quantitative reverse-transcriptional PCR, gene ‘knockdown’ via RNA interference, transfection and 59Fe uptake/efflux assays.

The aim of this projectis to determine the role of GPI-linked Cp in astrocytic Fe processing. This will have important ramifications for the understanding and treatment of neurodegenerative diseases that are associated with abnormal brain Fe metabolism, such as Alzheimer’s and Parkinson’s diseases, and the rare genetic disease, aceruloplasminemia.

Discipline: Pathology
Co-supervisors: Des Richardson
Keywords: Iron Metabolism, Cell & Molecular Biology, astrocytes