Parkinson's Disease
People with Parkinson's disease (some 120,000 in the UK) suffer from shaking, rigidity, balance problems and slowed movement. Similar symptoms that are a side-effect of other diseases are termed Parkinsonism. Much of what we know about Parkinson's disease comes from models of the disease in animals, usually mice.
> Therapy: Drug and dietary approaches
Studies in rats led to the basic discovery that the disease is caused by the lack of an essential substance, dopamine, within the brain. A medicine that aims to replace dopamine, levodopa, helps sufferers but is far from ideal. Research on rats indicates this is because the dopamine causes brain connections to become less responsive and therefore unable to process some signals. In 2002 research showed why: dopamine loss causes parts of the brain to reorganise and the brain becomes less able to process some signals. These are permanent changes that mean the condition will always be difficult to treat, shifting the emphasis to prevention1.
Parkinson’s symptoms can be induced in mice by three poisons: 6HD, rotenone (a natural pesticide extracted from root vegetables), and MPTP, a common contaminant of street drugs. They may all lead to overproduction of nitric oxide, a naturally occurring chemical that is harmful in quantity. Genetically modified mice that cannot produce nitric oxide are resistant to the effects of MPTP2. Therefore, blocking nitric oxide production in the brains of people susceptible to Parkinson’s may prevent or slow the disease. However, when stem cell therapy is used, nitric oxide is essential if new cells are to become ‘wired in’ (see below).
Animal studies have linked susceptibility to Parkinson’s disease with pesticide exposure and with removal of the ovaries3,4. Compounds called proteosomes, which remove dead material from cells, are susceptible to proteosome inhibitors. These are common environmental toxins, and therefore may be a contributory cause5.
Though most cases are probably due to a combination of genes and environment, a small proportion of human disease is essentially genetic. Recently, mice were genetically programmed to simulate both the symptoms and the brain alterations found in Parkinson’s disease6,7.
A new study has identified an important link between the two main inherited forms of the disease, in which the genes for either parkin or α-synuclein (αS) are mutated. We now know that both proteins interact with a third protein, synphilin, and the mutations disturb this interaction. Lewy bodies, found in patients’ brains and thought to be a cause of Parkinson’s, contain parkin, αS and synphilin. Researchers hope to reduce Lewy body formation by genetic enginerring8. β-synuclein inhibits αS in mice, and may in future be delivered to patients to reduce or prevent Parkinson’s disease9.
Studies of monkeys led to understanding of the entire nerve circuitry involved in human Parkinson's disease. Part of the problem in Parkinson's disease is that the loss of dopamine in a region called the basal ganglia causes the output system to seize up because other areas of the brain become too active. Switching off a specific part of the basal ganglia called the subthalamic nucleus can curb these effects. This is done by stimulating this brain area with tiny amounts of electrical current. A brain 'pacemaker', or Deep Brain Stimulation (DBS) of the subthalamic nucleus, reversed and improved the movements of monkeys with Parkinson’s disease10. This advance has proved effective on effective on human patients11 and was approved by the US Food and Drug Administration in January 2002. The benefits are often immediately apparent and quite dramatic. Over 20,000 Parkinson patients worldwide had been treated with DBS and the treatment is available in the UK to patients whose symptoms cannot be controlled by drugs.
Therapy: drug and dietary approaches
Caffeine consumption seems to have a protective effect12. Research in mice suggests that a diet deficient in the B vitamin folic acid may raise the risk of Parkinson’s disease. The researchers recommend patients take 400 μg daily supplements13. An epilepsy drug, D-beta-HB, restores impaired brain function in Parkinson’s mice and might therefore have a protective effective in humans14.
A modified tetracycline antibiotic called minocycline appears to prevent Parkinson-like brain cell loss in MPTP-treated mice. However, the antibiotic doesn’t enter the brain readily and the mice therefore needed high doses, so a better approach would be to develop a different tetracycline that gets into the brain more easily15.
Meanwhile, an experimental drug is under development that counteracts the adverse effects of levodopa. BB897 partly mimics dopamine but eases its side effects, which are involuntary movements of the mouth and limbs. It is expected to go into clinical trials soon16.
Transplants of fetal brain tissue have been tried with some success, but there are obviously ethical problems. These may be overcome by cloning stem cells, which are cells, usually embryonic cells, that have the potential to develop into all cell types found in the body17. Having succeeded in treating multiple sclerosis this way in mice18, researchers then took advanced stem cells from rats, which had already started on the path to becoming nerve cells, and induced them to develop into dopamine-producing brain cells19, which survived for two weeks in mouse brains. If human stem cells can be coaxed to behave in the same way, there is a potentially unlimited source of dopamine-producing nerve cells to treat Parkinson’s patients.
In 2001 researchers made cultures containing 80% mouse nerve stem cells, compared with 5% using previous methods. The cells were transplanted into developing mouse brains, where they made nerve and supporting cells20. Then, scientists showed that embryonic stem cells transplanted into rat brains will develop into various brain cells, and that they relieved Parkinson’s-like symptoms. Over half the rats got better, and at autopsy several months later had new brain cells. A few rats died with non-malignant tumours at the injection site and the scientists are now trying to prevent this21. Scientists have coaxed monkey embryo stem cells to form dopamine-producing brain cells in a test tube22.
In the early studies, stem cells were mainly found to have become support cells called glia, rather than new neurons. Only a few brain areas normally add new neurons during adult life and these seem to contain the signals that allow stem cells to mature into neurons; cultivating stem cells in a glass dish with a cocktail of growth factors and other proteins for a day before transplantation seems to enhance their ability to become neurons23.
New nerve cells have not only to be supplied to the brain, they must also be wired-in to its circuitry. In 2003 researchers using rats found that nitric oxide, a simple molecule that plays many roles in animals, is essential for new nerve cells to become ‘wired in’ and functional24. Further research showed that nitric oxide also shuts down a protein, called parkin, which plays a role in the development of Parkinson’s disease25.
Brain stem cells are immune privileged, which means they can be transplanted without being rejected by the immune system. When brain stems cells from one strain of mice were transplanted to the kidneys of another strain, they were not rejected26. This shows that human transplants are probably feasible without the need for immune-suppressing drugs.
Two genes required for production of dopamine in the brain were injected into the brains of Parkinsonian mice, resulting in a considerable improvement in their condition without any need for other treatments27. Symptoms were also reduced in monkeys that received the gene for GDNF28. About a year later, in April 2002, scientists reported reducing and even reversing Parkinson’s symptoms in mice by injecting genes into rats’ brains, stimulating them to make dopamine. In the experiments, researchers tried two genes that increase dopamine production and a so-called promoter—a section of DNA that enhances the expression of the genes. The findings suggest that this treatment may be an effective tool to reduce the effects of Parkinson’s29.
Following successful animal tests, doctors performed the first-ever human trial of gene therapy for Parkinson’s disease. The technique uses the GAD gene, which makes a molecule called GABA, to inhibit a specific group of overactive brain cells. The GAD gene was delivered by a modified virus and functioned effectively, so that treated rats did not continue deteriorating, unlike the untreated control rats. Tests on monkeys showed the therapy to be safe30. In September 2004 the first patient had passed one year without a hitch. Nathan Klein claimed to have experienced an improvement of 40–60% in overall symptoms when he is on his medication, and 10–20% when he is not. He suffered from a right-side tremor before surgery31.
Scientists have genetically engineered mice to produce symptoms similar to those of human patients suffering from multiple system atrophy (MSA), also known as Shy-Drager syndrome. It is related to Parkinson’s disease and affects 5000 people in the UK. Some brain cells that surround nerve fibres produce a protein called α-synuclein (αS), and these cells die as the individual ages. Transplanting the human gene for the αS protein into the mouse genome prevents this death. This will help us to understand more about the disease and help researchers to develop and test drugs against multiple system atrophy32.
September 2004
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20. Rietze RL, Valcanis H, Brooker GF et al (2002) Purification of a pluripotent neural stem cell from the adult mouse brain Nature 412, 736
21. Björklund LM, Sánchez-Pernaute R, Chung S et al (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model Proc Nat Acad Sci 99, 2344
22. Kawasaki H, Suemori H, Mizuseki K et al (2002) Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity Proc Nat Acad Sci 99, 1580
23. Wu P, Yevgeniya I. YI, Gu Y et al (2002) Region-specific generation of cholinergic neurons from fetal human neural stem cells grafted in adult rat. Nature Medicine 5, 1271
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25. Chung KK, Thomas B, Li X et a l (2004) S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science 304, 1328
26. Hori J, Ng TF, Shatos M et al (2003). Young neural progenitor cells lack immunogenicity and resist destruction as allografts. Stem Cells 21, 405
27. Szczypka, MS, Mandel RJ, Donahue BA et al (1999) Viral gene delivery selectively restores feeding and prevents lethality of dopamine-deficient mice Neuron 22, 167
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30. Luo J, Kaplitt MG, Fitzsimons HL et al (2002) GAD gene therapy in a Parkinson's disease rat model Science 298, 425
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32. Kahle PJ, Neumann M, Ozmen L et al (2002) Hyperphosphorylation and insolubility of a-synuclein in transgenic mouse oligodendrocytes EMBO reports 3, 583
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Research Fields: Biochemistry, Genetics, Brain & nervous system, Drugs & toxins(yes - 4 items)Animals Used: Rat, Mouse, Mouse (knockout/GM)(required - 3 items)
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