Metal ions in proteins potential cause of disease

Saturday 8 March 2008 12:00AM (view full episode)

Copper-containing proteins play important roles in organisms ranging from bacteria and yeast to plants and animals. The objective is to understand the properties and biological functions of wild type copper-zinc superoxide dismutases (CuZnSOD) and to understand why mutant human CuZnSOD proteins cause familial amyotrophic lateral sclerosis.


Robyn Williams: Well Stephen Hawking, the Cambridge astrophysicist, is now half robot, half paralysed, shrunken body as a result of motor neuron disease. No hope of cure in sight...until last week, from two sources.

[excerpt from AM]
Peter Kay: Good morning, this is AM, I'm Peter Kay. Australian scientists have made an important discovery about what causes the devastating illness motor neurone disease. They've found it's an abnormal gene which kills the nerves from the brain to all the muscles in the body. National medical reporter Sophie Scott is speaking to Professor Garth Nicholson from the Anzac Research Institute.

Garth Nicholson: Some years ago it was found that a particular protein was present in large amounts in the spinal cords of people with motor neurone disease and associated dementia, which is often occurring with motor neurone disease. This protein's called TDP43. So we looked at TDP43 in families with motor neurone disease because we didn't know whether the protein found in the spinal cord was trying to help the body recover from the disease or poisoning the body. This was the smoke that it had something to do with motor neurone disease and we've actually found the fire, because we have proven in the families that have motor neurone disease with a mutation in this gene, this causes motor neurone disease.

Sophie Scott: So how important is that, given that we haven't really known what causes this disease up until now?

Garth Nicholson: Many people have thought for years that motor neurone disease might be some poison of some sort in the environment. But here we've been able to show that it seems to be a poison in the body itself. Something's going wrong, so the mechanism actually becomes dangerous and leads to the death of neurones.

Sophie Scott: What are the implications of that for things like prevention or treatment?

Garth Nicholson: If we're right, this opens up a chance of trying to reduce this protein or get rid of it or prevent it. And then you'd have either a prevention or a cure for the disease.

Sophie Scott: At the moment what's the situation with either treating patients with motor neurone or offering them some hope?

Garth Nicholson: Motor neurone disease is probably many diseases and some varieties are extremely lethal, killing people in three months, and some varieties go for years and years-doesn't really kill people. So there's a big variation in motor neurone disease and this may reflect all different varieties of motor neurone disease with different mechanisms. But if there's an underlying mechanism that's common to all, then you've got a chance of a treatment. And because this protein is found in all motor neurone disease, this does offer some hope that we might find a general treatment for all.

Robyn Williams: And Garth Nicholson, of the Anzac Institute at the University of Sydney tells me that's the clue; many common diseases have lots of different causes. And the challenge for the scientist is to find a pattern.

Dr Nicholson has been looking at the genetic end. Joan Valentine in Los Angeles has been starting with the chemicals, the poison itself. And she emphasises how unusual Stephen Hawking has been as a victim of motor neurone disease.

Joan Valentine: Stephen Hawking is very unusual in living so long with the disease. Most people who have the disease do not live very long after the diagnosis. And they're very interested in what science may be doing, even if it's not going to benefit themselves, they're very interested in hoping that there's going to be a cure some day. It's very affecting, and the graduate student researchers have been very inspired to work even harder on their research.

Robyn Williams: That's Professor Joan Valentine. She was analysing the chemical structure of proteins, just for basic interest, to see how the metals were tagged on, when it became known that there was a link with the disease. Then it all took off.

Joan Valentine: I was an inorganic chemist (still an inorganic chemist) and interested in metal complexes. Not interested, actually, in anything biological. But then this protein was described in the literature and it bound both copper and zinc in a very interesting coordination environment. And so I was curious; I started working on it. And it kept on going from there.

Robyn Williams: An awful lot of people who know science say that if you do excellent basic research you find that it often-invariably in fact-leads somewhere. Now what happened when you were reading The New York Times and saw a mention of your protein?

Joan Valentine: I will admit that over the years working on this protein I did get interested in the biology. But certainly I had no idea that our research would be related to anything of any health relevance. I was just interested in how the protein worked. But then in March of 1993 my husband was reading The New York Times and he said to me, 'Hey, Joan, looks like superoxide dismutase is involved in Lou Gehrig's disease.' I said, 'No, that can't be right.' So he showed it to me, and so immediately...they said superoxide dismutase...well, it turns out that there's a manganese superoxide dismutase as well as a copper zinc superoxide dismutase. And I work on the copper-zinc superoxide dismutase, so that day I went in to work, I spent all day trying to track down somebody who knew if it was our protein that actually was related to Lou Gehrig's disease, and this involved calls to Harvard and MIT and finally I tracked down somebody who said yes, it was our protein. So it was a very exciting day.

Robyn Williams: And what happened next, as a result?

Joan Valentine: Well, it turns out that in our research we'd started out from a very inorganic chemical point of view and characterised the protein, the copper and the zinc. And as our interest in this developed, also the tools of molecular biology had developed, enabling one to do protein redesign. And so we had been taking the protein and redesigning it by mutagenesis to see what effect that would have on the copper and the zinc. So in my laboratory we had the skills to make mutant forms of the enzyme. And what The New York Times was saying, and then the article in the scientific literature that followed it, was that mutations in this enzyme were causing the protein to be toxic and cause Lou Gehrig's disease. So we knew how to make these mutants and we immediately started making the disease-causing proteins in order to figure out what effect these mutations would have.

Robyn Williams: Do it indicate at that stage that linked to a protein obviously there might be one or more genes and therefore there's a kind of genetic syndrome going on there, hence the mutation and hence the changed protein?

Joan Valentine: Yes. That's exactly right. It turns out like a lot of other neurodegenerative diseases, Lou Gehrig's disease, or ALS (amyotrophic lateral sclerosis), has a familial form which is genetic, it's linked to a gene, and a sporadic form. And back in 1993 nobody had any idea what caused any ALS except it was known that some of it was genetic. So this was the first breakthrough in actually finding a cause. And this would be a genetic form of ALS.

Robyn Williams: Any tests done on animals, to see whether your mutant forms caused problems?

Joan Valentine: Yes, actually we were not the ones who developed the transgenic mice, but the discovery of the mutations in the gene caused the disease enabled other investigators to make transgenic mice where they took the human gene that was found in the people with the disease and they put it into mice and showed that it caused the same disease. This then enabled them to have an animal model in which they could test out hypotheses and has really enormously advanced the field.

Robyn Williams: What is the protein actually doing, because the nervous reaction, obviously, the breakdown in the nervous system, is something that's quite profound, to do with the conduction of impulses and so on. So how much is known now about how much that protein is involved with organically in the body?

Joan Valentine: This is the real irony about this enzyme and this disease, and that is that the normal function of this enzyme has a very beneficial function, it's an antioxidant enzyme. It reacts with the superoxide and protects against oxidative damage. So the first thing you'd think of was, well, mutations must be inactivating it and that's why you get the disease. But it turns out that's not true. It turns out what's actually happening is the mutations are changing the enzyme and making it toxic in some way. Based on the transgenic mouse studies it actually looks as though this disease is a protein aggregation disease, and so what is happening has nothing to do with superoxide but actually to do with the protein forming toxic aggregates, like Alzheimer's disease and Parkinson's disease, for example.

Robyn Williams: Does that give you any leads as to treatment? I know you're a chemist but are your colleagues working on that sort of front?

Joan Valentine: Well, yes. And in fact it's interesting, because many of these neurodegenerative diseases that are believed to be diseases of protein folding have similarities and people are hopeful that one will be able to find drugs that can slow down this protein aggregation process. And it's actually possible that drugs that are effective for some of the diseases may actually be effective for the others. And there's a lot of attention now to drug screening to try and slow down this process for all of these diseases.

Robyn Williams: Yes, I remember talking to a professor of chemistry in Cambridge (in England, not in Harvard) who was looking at this global picture of the proteins, and their shape, of course, because a whole family are involved in such diseases, suggesting that if you find the key to one, who knows, it might lead you to many of the others. It's still a long way off though, isn't it?

Joan Valentine: I can imagine that was Chris Dobson, is that right?

Robyn Williams: Yes, it was Chris Dobson. You're absolutely right.

Joan Valentine: He's done some beautiful work, real fundamental work, and I think he's right, this is a general property of proteins and when it starts breaking, when we really understand how to control this, it's going to have very widespread implications in disease.

Robyn Williams: Joan Valentine, professor of chemistry at the University of California, Los Angeles. And Lou Gehrig was the famous baseball player who, like Stephen Hawking, succumbed to motor neurone disease. But now at Cambridge, Los Angeles and Sydney secrets are being revealed, and maybe the disease in all its varieties will come under control.


Joan Valentine
Professor of Chemistry and biochemistry
Los Angeles CA USA


Robyn Williams
David Fisher