New research offers hope of a cure

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The knowledge explosion in the field of Parkinson's has resulted in better animal models, faster testing systems and new possible treatments. Researchers therefore have every hope of finding a cure for the disease.

The new genetic knowledge has opened completely new doors with respect to research into the causes of Parkinson's disease, according to Thomas Perlmann, Professor of Molecular Developmental Biology at Karolinska Institutet's Department of Cell and Molecular Biology.

Previously, animal models for Parkinson's disease were used in which the dopamine cells in the brain were knocked out by toxic substances.

"These are poor models for Parkinson's. It is true that the dopamine cells become acutely ill, but not in the same way as with Parkinson's disease," he says.

Instead, the discovery of the mutation in the gene for the protein alpha-synuclein and its direct impact on disease progression has pointed to a new way to develop better animal models. Alpha-synuclein is the primary content of what are known as Lewy bodies, protein accumulations, which occur in the cells of a majority of all Parkinson's patients.

Bild på Thomas Perlmann"Even in cases where there is no genetic mutation, alpha-synuclein is still present in the Lewy bodies. The protein accumulation seems to be central to the clinical picture and this can be reproduced very effectively in animal models," says Thomas Perlmann.

In these, the animals develop a clinical picture similar to Parkinson's that can be used both to study the disease and possible treatments.

For example, Thomas Perlmann talks about one of his projects to do with a specific transcription factor, Nurr1, which is important for enabling the dopamine cells to develop. His research team has been studying it for a number of years. In collaboration with researchers from Lund, they recently discovered that the Nurr1 protein is down-regulated in laboratory animals that overexpress alpha-synuclein.

"It is a very interesting result that links alpha-synuclein and Nurr1." He is now also able to demonstrate that if the gene for Nurr1 is added to the animals, the dopamine cells are preserved and the Parkinson's-like symptoms disappear almost completely. It is, in other words, a treatment that slows progression, but translating the discovery into a treatment method is not as simple as one might hope.

"Nurr1 is a transcription factor that is normally found inside the cell nucleus and is nothing you can eat or even inject into the blood. It does not get into the cells. One possibility, of course, is gene therapy that we use on the animals, but this involves some practical difficulties to do with injecting viral vectors into the brain in humans. Once you've injected them, you have introduced a permanent change, and it will require very careful experiments on animals before this type of gene therapy can be tested in humans," says Thomas Perlmann.

The discovery is very interesting, but Thomas Perlmann does not want to claim any early victories as he well aware that successful animal experiments do not always lead anywhere.

"There are risks associated with animal models. The animals might be so different from us that they leave the wrong message," he says.

Stem cells an interesting line of research

Another very interesting line of research is stem cells. The idea is to cultivate and transplant new dopamine cells to brains affected by Parkinson's and so increase dopamine production and gain symptom-free years.

The principle has already been proven to work by transplanting brain cells from aborted fetuses, known as embryonic stem cells, but the method has several drawbacks. Firstly, the patients' immune systems have to be suppressed with drugs so that the new cells will not be rejected and, secondly, there is a very limited availability of fetuses.

Bild på Ernest Arenas."The advantage of stem cells is that you can cultivate them and obtain as many cells you want," says Ernest Arenas, Professor of Molecular Neurobiology at Karolinska Institutet's Department of Medical Biochemistry and Biophysics.

No stem cell transplantations have yet been carried out on humans with Parkinson's disease, but researchers have high hopes for the method. The scientific advances that led to last year's Nobel Prize in Physiology or Medicine have opened up opportunities to take ordinary skin cells from individual patients, revert their development to that of pluripotent stem cells and then, with the right additives, make them develop into dopamine cells for transplantation into the same patients. This would avoid the problem of immunological rejection. On the other hand, there is a disadvantage in using the patient's own cells if the disease has a genetic origin. In that case, the skin cells would have the same mutations.

"Perhaps those cells will develop the disease more quickly. No one knows yet because it has not been done," says Ernest Arenas.

But he says that if that were to happen, another possibility would be to use stem cells from healthy donors or from embryos to cultivate a sort of dopamine cell bank from which it is possible to select cells that are so similar to the patient's own that they would be accepted by the immune system.

A further step is what is known as direct reprogramming.

"Here, you take a skin cell and reprogram it straight into a dopamine cell without reverting it to a stem cell. Some research teams around the world have shown that it is possible," says Ernest Arenas.

And if it is possible, is not a distant thought to reprogram existing cells directly in the brain.

"Then you could reprogram astrocytes straight into dopamine cells without the need for transplantation at all. But then you'd need to use gene therapy," says Ernest Arenas.

However, he admits that this is more of a dream that lies far ahead than a realistic goal for the foreseeable future. Whatever happens with these visions of the future, there is one, perhaps even more important, area of application for stem cells that is already in full use. This concerns the direct testing of potential drugs on stem cells that have Parkinson's disease.

"In that way, you get the disease in a petri dish," says Ernest Arenas.

Drugs can be mass produced

Most major pharmaceutical companies conduct research in this field whereby they are able to quickly test large numbers of substances against Parkinson's disease and see if there is any change in the affected dopamine cells

Ernest Arenas realises that no matter how much stem cell transplantation technology develops, it will be a limited form of treatment in comparison with a new drug that can be mass-produced. This is especially the case as those who should preferably receive the transplant are the younger, recently diagnosed.

"One of the disadvantages of stem cell therapy is that it includes surgery for a disease that is relatively benign, especially in the beginning," he says.

But in the absence of better drug treatment, transplanting stem cells could improve the quality of life for many patients. For at present, there is a shortage of new drug treatments that really change the situation for Parkinson's disease.

There are around ten substances being tested in humans where it is hoped that they might have that effect, but it is still far too early to determine if any of them will meet expectations. But the scientists will continue researching until they have found a solution.

"The ultimate goal must surely be to cure the disease," says Thomas Perlmann.

Text: Fredrik Hedlund. Published in Medicinsk Vetenskap 2/2013