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Parkinson's Disease

There are approximately 6 million people with Parkinson’s disease worldwideANCHOR, although estimates range from 5-10 million. The symptoms include shaking, rigidity, balance problems and slowed movement. Parkinson’s disease is known to be caused by the death of brain cells that produce a certain neurotransmitter known as dopamine. These cells are in the substantia nigra, an area of the brain. The lack of dopamine affects the control of nerves responsible for movement. These symptoms appear once 70% of the cells have died, which makes early interventions highly important. Much of what we know about Parkinson's disease comes from models of the disease in animals, usually mice.

Dopamine and levodopa
Environmental factors
Genetic factors
Deep brain stimulation
Drug and dietary approaches
Stem cell research
Gene therapy
References

Dopamine and levodopa

Discovering the role of dopamine in the brain’s control of movement and its link to Parkinson’s disease was Nobel prize-winning work. Arvid Carlsson studied rabbits that had been given a drug that removes dopamine from their brain. He had hoped to see some effect on their movement, and indeed the rabbits went into complete stuporANCHOR. The rabbits’ movement could be restored by injecting them with levodopa (or L-dopa), a chemical that the brain converts into dopamineANCHOR.

When later studies by CarlssonANCHOR and others revealed that a lack of dopamine was the root cause of Parkinson’s disease, researchers could treat patients with levodopa just as they had with the rabbits.

Although levodopa helps some sufferers, its effects wear off over time. Research on rats indicated 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 preventionANCHOR.

Another way to boost dopamine levels is taking drugs known as monoamine oxidase (MAO) inhibitors. There are currently two MAO inhibitors available: selegiline and rasagiline. They can be used in mild, early cases of Parkinson’s on their own and delay the need for L-DOPAANCHOR, or can be taken in combination with L-DOPA to improve symptoms and slow the development of dopamine resistanceANCHOR. Selegiline was the first MAO inhibitor to be used in this way, but in an attempt to avoid some of the neurotoxic side products of selegiline, researchers developed rasagilineANCHOR. Rasagiline was shown to increase dopamine levels in ratsANCHOR ANCHOR.

The video below shows how marmosets are used to study the effects of dopaminergic drugs:

Environmental factors

Parkinson’s symptoms can be induced by three chemicals: 6-OHDA, 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 MPTPANCHOR. Therefore, blocking nitric oxide production in the brains of people susceptible to Parkinson’s may prevent or slow the disease.

The effects of MPTP were discovered after several drug addicts appeared to develop Parkinson’s disease. It was traced back to an MPTP impurity in MPPP, a synthetic opioid drug. The MPTP was found to destroy the substantia nigra and killing dopamine-producing neurons. MPTP has since been used to develop animal models for Parkinson’s disease, particularly in mice and marmosets.

Rotenone, a potent pesticide, was first discovered to cause Parkinsonism in ratsANCHOR. In that study, the rats were injected with rotenone over 5 weeks and appeared to be a useful model for Parkinson’s disease. Further research in rats and cell cultures showed that prolonged exposure to rotenone could also trigger ParkinsonismANCHOR ANCHOR ANCHOR, and in 2011 a health study showed a link between Parkinson’s disease in farm workers and the use of rotenoneANCHOR.

Genetic factors

Though most cases are probably due to a combination of genes and environment, a small proportion of human disease is essentially genetic. Mice can be genetically programmed to simulate both the symptoms and the brain alterations found in Parkinson’s diseaseANCHOR ANCHOR.

Mutations in the protein LRRK2 are the most common cause of inheritable Parkinson’s disease. Although it accounts for only 2% of all cases of Parkinson’s in Western countries, this rises to 20% and 40% for Ashkenazi Jewish populations and North African Berber ancestry respectivelyANCHOR ANCHOR. Mutated forms of LRRK2 block the disposal of old, damaged proteins which then clump together in nerve cells and cause further damage.

A study has identified an important link between the two other 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 engineeringANCHOR. β-synuclein inhibits αS in mice, and may in future be delivered to patients to reduce or prevent Parkinson’s diseaseANCHOR.

Deep brain simulation

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 diseaseANCHOR. This advance has proved effective on effective on human patientsANCHOR and was approved by the US Food and Drug Administration in January 2002. The benefits are often immediately apparent and quite dramatic. Over 80,000 patients worldwide have been treated with DBSANCHOR and the treatment is only available to patients whose symptoms cannot be controlled by drugs. In the video on the right, Mike Robbins demonstrates how deep brain stimulation helps him to control the symptoms of Parkinson's disease.

 
It is hoped that this treatment can be expanded to more patients by making the surgery less invasive. Recent research in mice and rats has shown that the DBS effect can be created by stimulating fibres in the spinal cordANCHOR. The technique, known as dorsal column stimulation, was first demonstrated in two different animal models of Parkinson’s disease – a genetically modified mouse and a chemically-induced rat model – and both showed marked improvement through the spinal stimulation. This has since been trialled in 18 Parkinson’s patients who have shown improvements in motor symptoms, gait and postureANCHOR ANCHOR ANCHOR ANCHOR.

There is even hope that surgery could be avoided altogether. Research in rats has suggested that the neurons activated by DBS are close to the surface of the brain, rather than at the site of the electrodeANCHOR. This means that these neurons could be reached by transcranial magnetic stimulation or similar techniques, where an electric field is created in the brain by applying a magnetic field outside the skull.

Drug and dietary approaches

Epidemiological studies on the population suggested that consuming caffeine reduces the risk of developing Parkinson’s diseaseANCHOR ANCHOR. This effect was further examined in a study of MPTP mouse models of Parkinson’s, which demonstrated that caffeine reduces the symptoms and works by blocking the A2A adenosine receptorANCHOR. There are now several A2A adenosine antagonists in clinical trials, and one known as Istradefylline has been approved for treating Parkinson’s in JapanANCHOR. In addition, a clinical trial of over 60 patients showed that a caffeine pill, equivalent to 3 cups of coffee a day, taken over 6 weeks, reduced tremors and improved mobilityANCHOR.

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 supplementsANCHOR. An epilepsy drug, D-beta-HB, restores impaired brain function in Parkinson’s mice and might therefore have a protective effective in humansANCHOR.

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 dosesANCHOR. Early clinical studies have shown that the drug does not have harmful effects, but further, larger trials will be needed to determine if it benefits neuroprotectionANCHOR.

Stem cell research

Stem cells are able to transform into different types of cells and it is hoped that they could be used to replace the lost dopamine-producing cells in patients with Parkinson's disease. Much of the initial research on these focused on using stem cells from embryos, as this was the most common source for them. This showed success in animal models of Parkinson's, with new nerve cells and dopamine-producing cells developing in the brainANCHOR ANCHOR ANCHOR ANCHOR ANCHOR ANCHOR. In one trial, monkeys given human embryonic stem cells showed dramatic improvement in their symptoms. Some were unable to move beforehand but were able to walk and feed themselves following treatmentANCHOR. Intriguingly, only a small proportion of the implanted cells became new dopamine-producing neurons while others became astrocytes – helper cells that help to support others and promote healing.

Since 2006, researchers have been able to transform specialised adult cells (often skin cells) so that they become like stem cells. These induced pluripotent stem (iPS) cells have provoked a great deal of research into this area. They are advantageous over embryonic stem cells as they avoid the ethical cost of harvesting from aborted foetuses and the iPS cells can be produced from the patients own cells, so they are a genetic match. However, further research is needed into iPS cells to better understand their limitations compared to true stem cells.

Research in monkeys has shown that iPS cells can be implanted into the brain without triggering an immune reaction, as long as the cells originally came from the recipientANCHOR. The scientists who carried out this research are now planning to start clinical trials in a small number of Parkinson’s patients in 2015ANCHOR.

Gene therapy

Gene therapy is technique for inserting genes into cells in order to either restore or boost function. This is viewed as a promising, yet difficult, approach for treating Parkinson's disease and there are currently two main approaches that have been takenANCHOR. The main approach is inserting genes that affect the activity of the neurons in the brain, by boosting production of dopamine or another neurotransmitter known as GABA (gamma-aminobutyric acid). An alternative technique is to try to repair the damaged cells or prevent further cells from becoming damaged.

The approach that progressed furthest is insertion of the GAD gene, which boosts GABA production. This was first demonstrated in rats in 2002ANCHOR and was followed by safety testing macaques ANCHOR ANCHOR, phase I clinical trialsANCHOR, and eventually double-blind phase II clinical trials in 2011ANCHOR. Although patients in the trial saw a 23% improvement on a standard test for Parkinson's symptoms, this was viewed as only a modest improvement and the program was discontinued by its sponsor NeurologixANCHOR.

An alternative approach is to insert genes that boost production of dopamine. The main target for this is the gene AADC, which is used to convert L-DOPA into dopamine. This approach was demonstrated in monkeys in 2000 ANCHOR before starting in clinical trials a few years later. This demonstrated that the technique was safeANCHOR ANCHOR, but there was only a modest improvement in symptomsANCHOR ANCHOR. This has been blamed on several factors including too low dosageANCHOR and a new clinical trial is due to be attemptedANCHOR.

AADC has also been used in combination with other genes known as TH and GTP-CH1, which together make up the main genes involved in dopamine production. Tests of this treatment showed good effectiveness in MPTP models of Parkinson’s in macaquesANCHOR. This was followed by a trial in 15 Parkinson’s disease patients, which showed modest improvements and no adverse effects related to the treatment ANCHOR. Like the AADC alone treatment, researchers are hoping to improve the method for delivering the virus into the brain before progressing to further trials.

Rather than attempting to boost dopamine production directly, researchers have also tried to boost repair and support the dopamine-producing cells by inserting the genes NRTN or GDNF.

There have so far been two phase II clinical trials for NRTN gene therapy, which aim to increase levels of the protein neuturinANCHOR ANCHOR ANCHOR. The first of these did not meet its targets by the end of the trial at 12 months, but seemed to show some success in patients who continued several months laterANCHOR. Following from research into animal modelsANCHOR ANCHOR, the trial was repeated with larger doses, refined targeting and longer time period. However, despite these changes the trial could not show benefit to the patients within statistical significanceANCHOR. It is still not clear why the results did not correlate between the animal studies and the clinical trials, but it does not appear to be due to insufficient dosageANCHOR ANCHOR. It has been suggested that Parkinson’s disease could prevent the neurturin protein from spreading throughout the damaged region, a problem that is not found in the animal modelsANCHOR ANCHOR ANCHOR.

There are trials for GDNF gene therapy, following the improvement of symptoms in monkeys through this techniqueANCHOR. However, the levels and distribution of GDNF in the body is similar to NRTN and so may face similar problems ANCHOR..


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