Guest Column with Dr Alexandra Grubman

November 12 / 99

Dr Alexandra Grubman is a research officer in the Department of Pathology.
Dr Alexandra Grubman is a research officer in the Department of Pathology.

Neurodegenerative diseases cause the suffering of millions of people worldwide. I work in a team of 20 scientists dedicated to discovering what causes these diseases and how we can potentially treat them. While our group is involved in several projects studying commonly known conditions such as Alzheimer's disease, we are also particularly interested in rare forms of neurodegeneration such as motor neuron and Batten's diseases. By identifying similarities between different neurodegenerative conditions, we hope to generate classes of compounds that are able to effectively target common disease-associated processes.

One of these common hallmarks of neurodegeneration is impaired metabolism of a number of biologically important metals, such as copper and zinc. Sufficient metals are needed to carry out cellular roles and enzyme functions. Cellular distribution of metals is tightly controlled by a number of metal transporters and proteins. However, in neurodegenerative diseases, the normal balance of these metals is impaired. Accumulation, deficiency or incorrect distribution of metals has been shown to contribute to disease processes in various neurodegenerative disorders.

Our research team has pioneered a new approach aimed at restoring normal metal metabolism in these conditions by bypassing the problem and delivering metals to the right place in the right form. This approach has been very successful in models of disease. Using specially designed compounds to deliver metals to the brain has successfully delayed onset of neurological symptoms and increased life span in mice suffering from Alzheimer's, Parkinson's, Huntington's and motor neuron diseases. This has been made possible through a close collaboration with a team of chemists at Bio21 Institute, who are able to manufacture new compounds for us to test in our models.

So where do I fit into this picture? Within this large team, I lead a small group working on discovering the causes and mechanisms of Batten's diseases. Batten's disease covers a group of hereditary neurodegenerative conditions in children. These children begin life normally but become blind, suffer seizures and die by the time they are teenagers. We don't know exactly what causes these symptoms or how to treat them. Our group has recently discovered that like most other neurodegenerative conditions, drastic changes to metal metabolism occur in several forms of Batten's disease. Using a combination of cellular, biochemical, imaging and molecular biology techniques, we have evidence to suggest a mechanism by which metals are incorrectly trafficked in diseased cells. This involves direct binding of the disease-associated protein, CLN6, to a metal transporter, which somehow results in loss of this transporter, leading to metal accumulation in the wrong cellular compartment. We are now working on deciphering the molecular consequences of this, and investigating ways to deliver metals to the correct location, to bypass the perturbed metal trafficking pathways.
Dr Alexandra Grubman is a research officer in the Department of Pathology.

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