The Calcium Connection with Neuronopathic Gaucher Disease

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Dr Tony Futerman is Associate Professor in the Dept of Biological Chemistry at the Weizmann Institute of Science in Israel and is currently carrying out research into the calcium connection with Type 2 and Type 3 Gaucher disease. This article is based on one printed in Helping Hands, the Newsletter of the US Children's Gaucher Research Fund.

In order to explain the relevance of my laboratory's findings to Type 2 and 3 Gaucher disease, I need to describe the basic research that we are doing.

In 1990 I started working at the Weizmann Institute on sphingolipids, the molecules that accumulate in the sphingolipid storage diseases, of which Gaucher disease is the most prevalent. In 1997 I was promoted to Associate Professor and today run a laboratory consisting of ten people. There are Japanese, French, Yugoslavian, Indian, Russian and Welsh students or postdoctoral fellows, and a number of Israelis working in my laboratory. So the laboratory is truly multi-national.

Calcium Release from Nerve Cells

Sphingolipids are important constituents of the cells that make up our bodies and are found at particularly high levels in the brain.

Until 1998 all of our work had been basic research, or science for science sake. In this kind of research, the goals are well-defined but are not necessarily oriented to solving a particular medical problem or to understanding a particular disease. It was of course always in the back of my mind that sphingolipids accumulate in various human diseases but I would be less than honest to say that this was a motivation for my research.

All that changed in 1998. At this time, Andreas Schwarz, a student from Germany, was doing an experiment in which he was removing brains from rats and growing isolated nerve cells (neurons) in culture dishes.

In the particular experiment that turned out to be so important, Andreas added a chemical compound to neurons that inhibits the activity of glucocerebrosidase, the enzyme that is defective in Gaucher disease.

He noticed, together with Ed Korkotian, a postdoctoral fellow in the Dept of Neurobiology, that when he added caffeine to these cells, there were quite stunning changes in calcium release from inside the nerve cells.

This finding was quite unexpected and led to considerable excitement. Might this explain some of the pathology in the brains of Type 2 and 3 Gaucher patients? I must admit that it took me some time to appreciate that it is simply not known how the brain is affected in this disease. Surely someone out there was doing some basic research? Could our studies begin to give some information about what is going on in patients?

That this might be the case was boosted by additional experiments in which we showed that nerve cells in which glucocerebrosidase activity was blocked were much more sensitive to various neurotoxic agents and this effect was directly related to the changes in calcium release that we had observed. Thus these Gaucher neurons died when we incubated them with neurotoxic agents.

Further Implications

The story became even more fascinating when we contacted Dr Raffi Schiffmann in the National Institutes of Health who told us that one of the neurotoxic agents that we use (the neurotransmitter glutamate) seemed to be implicated in neuronal dysfunction in his studies using human brain tissue obtained post-mortem from children who had died from this disease.

As a basic scientist, this is the first time that I have ever done anything that may be related to a human disease and in particular, that has the potential to explain some of the problems that occur in Types 2 and 3 Gaucher disease.

Calcium is also an important player in a number of neurodegenerative diseases, including Alzheimer's, so it should not be a surprise that it may play such an important role in Gauchers disease.

My research team and I are tremendously excited by these findings and having had no-one working on disease-related research three years ago, now most of my research team is focusing on this issue. We have more ideas at the moment that we can cope with or work on but the immediate goal of our research is to understand the calcium connection, not only in laboratory models, such as mice and rats, but also in human tissue.

Should our findings hold up after more research, then we may well be in a position to provide an explanation as to why brains are affected in Types 2 and 3 Gauchers disease and thus to provide clinicians with enough clues to devise possible therapeutic strategies that may eventually lead to a cure for this devastating disease.

The Board of Directors for the Children's Gaucher Research Fund has approved a $50,000 grant for medical research to Dr Futerman. The Fund is now trying to obtain another $50,000 from donors to match this amount.

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Source: Gauchers News March 2002.
© Copyright Gauchers Association 2002