Parkinson's Disease Biology and the Hope of Stem Cell Treatment
Brain Changes in Parkinson's Disease
What is Parkinson's Disease?
Parkinson's disease is a neurodegenerative disorder. It's caused by the death of cells in a part of the brain known as the substantia nigra. The cells make a chemical called dopamine while they are alive. Without an adequate supply of dopamine in the brain, a person experiences problems such as tremors, the inability to move quickly, muscle stiffness and balance problems.
Medications and other treatments can improve the symptoms of Parkinson's disease, but at the moment the disorder can't be cured. Unfortunately, the disease may be progressive. There is a hopeful development, however. Research suggests that using stem cells to replace the lost brain cells may be an effective treatment.
Parkinson's disease affects more men than women, although in my family my grandmother had the disease. It generally affects older people over the age of sixty, as it did in my grandmother's case, but younger people may be affected as well. Probably the most well known person affected by the disorder in North America is the actor Michael J. Fox. He developed young-onset Parkinson's disease at the age of thirty.
Although there are several theories to explain why brain cells die in Parkinson's disease, the ultimate cause of the illness is unknown. Many researchers think that the cause is likely a combination of a genetic mutation and an environmental trigger.
Parkinson's disease is named after James Parkinson (1755 - 1824), an English surgeon who first described the disorder. He called the disease shaking palsy or paralysis agitans. Parkinson was born on April 11th, which is now celebrated as World Parkinson's Day.
The Substantia Nigra and Lewy Bodies in Parkinson's Disease
In a person with Parkinson's disease, there is a massive death of cells in the substantia nigra. The substantia nigra is crescent-shaped and is located in the midbrain, which is the blue area in the illustration above.
In real life the substantia nigra is black in colour due to the presence of a pigment called neuromelanin inside neurons, or nerve cells. The area contains many dopamine-secreting neurons that send signals to other parts of the brain in order to regulate movement. When about 80% of the dopamine-secreting neurons in the substantia nigra die, symptoms of Parkinson's disease appear.
Although the substantia nigra gets most of the publicity when Parkinson's disease is discussed, researchers have discovered that some of the brain neurons that secrete norepinephrine die as well. This death may be responsible for disease symptoms such as digestive problems and a rapid drop in blood pressure when the person stands up after sitting or lying down (postural hypotension).
There is another frequent hallmark of Parkinson's disease besides cell death. Research indicates that the brains of many people with the disease contain abnormal clumps of protein called Lewy bodies. The most abundant protein in Lewy bodies is alpha-synuclein. The reason why the clumps form and their role in the disease isn't known, although there are several theories to explain their presence.
What is Dopamine?
Dopamine and norepinephrine are neurotransmitters. A neurotransmitter is a chemical that is produced at the end of a neuron when a nerve impulse arrives. The neurotransmitter travels across the tiny gap between neurons and binds to receptors on the next neuron, where it causes the generation of another nerve impulse. In this way signals travel from one nerve cell to another.
Dopamine is involved in transmitting signals that regular both our movement and our emotional response. This is why some people with Parkinson's disease experience mood disorders as well as muscle problems.
A common treatment for Parkinson's disease is a medication called L-dopa, or levodopa. This substance is changed into dopamine in the brain. Giving patients dopamine as a medication isn't effective because dopamine can't enter the brain. Its passage is blocked by the presence of the blood-brain barrier. This barrier is made of tightly joined cells lining the blood capillaries in the brain. The cells allow only certain substances to leave the blood and enter the brain. Luckily, L-dopa is able to cross the blood-brain barrier.
L-dopa is generally mixed with a chemical called carbidopa. Carbidopa inhibits enzymes in the digestive tract and blood vessels that can break down L-dopa. This allows the medication to reach the brain. Carbidopa can't cross the blood brain barrier.
Dopamine is a fascinating chemical that produces many different effects in the body. These effects depend on the specific neural pathway that uses dopamine as a neurotransmitter.
Living with Young-Onset Parkinson's Disease
What are Stem Cells?
Mature cells in an adult's body are highly specialized for particular functions and can't reproduce. The consequences may be serious if many specialized cells die in a particular area of the body and aren't replaced, as happens when dopamine-secreting neurons die in the substantia nigra.
Stem cells are unspecialized but have the ability to produce specialized cells. One example of normal stem cell activity in our body occurs in the red bone marrow inside certain bones. Stem cells in the bone marrow divide to produce new blood cells to replace the ones that have died.
Although stem cells are widespread in our body, they don't exist everywhere. This means that not all of our body cells can be replaced naturally when they die. However, scientists have found stem cells that can be stimulated artificially to produce the specialized cells that we need, including the neurons found in the substantia nigra. Stem cells are tantalizing for medical researchers because they offer the hope of replacing body cells that have been destroyed by disease.
Types of Stem Cells
Human stem cells are classified based on their ability to produce other cell types.
A totipotent stem cell can produce all types of cells in the body as well as cells in the placenta, allowing for the formation of an entire organism. The fertilized egg cell and the cells of the very early-stage embryo are totipotent. The embryo at this stage consists of a ball of undifferentiated cells called a morula.
A pluripotent stem cell can produce all types of cells in the body but isn't capable of producing placental cells or an entire organism. By four to five days of age the human embryo consists of a ball made of an outer layer of cells surrounding an inner cell mass and a cavity, as shown in the video below. The ball is known as a blastocyst. The cells in the inner cell mass are pluripotent and can be used as embryonic stem cells.
A multipotent stem cell can produce several cell types within one particular tissue instead of any type of cell in the body. Stem cells in an adult's body are multipotent.
Stem Cells and their Uses
Embryonic Stem Cells
Embryonic stem cells are a useful type of stem cell for repairing the body because they are so versatile. They are also the most common type of cell used in stem cell technology at the moment.
The embryos used in stem cell research and technology are obtained from the in vitro fertilization or IVF procedure. The purpose of this procedure is to enable a couple to have a baby when the natural method has been unsuccessful. The couple donate eggs and sperm, which are united in laboratory equipment. Multiple embryos are produced. Some are inserted into the woman's uterus in the hope that at least one will implant and produce a baby. Embryos that aren't needed are frozen or discarded. A couple may choose to donate these extra embryos to science.
New embryos aren't needed every time a lab needs embryonic stem cells. Stem cells have the ability to produce more stem cells by cell division. This means that labs can create multiple cultures of embryonic stem cells from one donation. Stem cells also have the ability to undergo a series of cell divisions that produce successively more specialized cells and eventually the fully specialized target cells.
Scientists are investigating the triggers that "tell" a stem cell to either make more stem cells or to make specialized cells. They are also investing the triggers that tell a stem cell which specialized cells to make. The research is very important because it has the potential to revolutionize the treatments for some serious diseases.
Induced Pluripotent Stem Cells, IPS cells or IPSCs
Embryonic stem cells are obtained from embryos that are not destined to develop into humans. However, given the proper environment, the embryos could continue their development and become human beings. For this reason, destroying an embryo to obtain the cells in its inner cell mass is strongly opposed by some people.
A method to induce adult human cells to become pluripotent stem cells has been discovered. Using IPS cells avoids the controversy surrounding the use of embryonic stem cells. There is some concern about the safety of IPS cells, however, since the process of inducing pluripotency involves the genetic reprogramming of cells. Inactive genes must be activated so that the cells return to a state that resembles that of an embryonic stem cell.
The technique for creating IPS cells was discovered by Shinya Yamanaka in 2006. In 2012, he won a Nobel Prize for his discovery.
Stem Cells and Parkinson's Disease
Researchers at Lund University in Sweden have made what may be a very significant discovery. In a recent experiment they destroyed some of the nerve cells that make dopamine in the brain of rats. This simulated the situation in Parkinson's disease and caused the rats to develop movement problems.
The researchers then stimulated human embryonic stem cells to become neurons that produced dopamine. These neurons were inserted into the damaged areas of the rat brains. The neurons survived inside the rats. Furthermore, after five months the implanted neurons had formed connections with other neurons and the amount of dopamine produced by the brain was normal. Most importantly, the movement problems of the rats had disappeared.
The press release about the experiment doesn't mention how many rats were involved or the percentage of rats that recovered, but the news is certainly exciting. However, clinical trials are needed to see if the process works in humans. These trials may begin as early as 2017. This may seem like a long time in the future for people with Parkinson's disease, but researchers must demonstrate that a clinical trial is safe and has a reasonable chance of being beneficial before health regulation agencies allow the trial to take place.
Stem Cell Transplants for Parkinson's Disease at Lund University
Fetal Cell Transplants for Parkinson's Disease
One concern with transplanting stem cells into the brain of a person with Parkinson's disease is that we don't know why the original brain cells died. Since we can't treat the cause of cell death, the transplanted cells might be killed, too. Tests with fetal cell transplants have shown that this won't necessarily happen, however.
Dopamine-secreting cells have been obtained from the brains of fetuses from terminated pregnancies and inserted into the brains of people with Parkinson's disease. The results of these trials have been mixed, but in at least some people the fetal cells have stayed alive and secreted dopamine. The research project referenced below states that two patients have had motor improvements for eighteen years after a fetal cell transplant. In addition, they no longer need to take dopamine-boosting medication to relieve their symptoms.
The use of fetal cell transplants to treat Parkinson's disease is still being investigated and sounds promising, although it seems to be even more controversial than the use of embryonic stem cells.
A Stem Cell Expert Talks about Parkinson's Disease
Stem Cell Treatments in the Future
The good news is that more than one group of scientists has been able to stimulate embryonic stem cells to produce dopamine-secreting neurons. This is an amazing achievement, since embryonic stem cells have the capability to produce a huge variety of cells. Additional requirements are needed in order to help people with Parkinson's disease, however. When the neurons are placed in the patient's brain, they must stay alive, form appropriate connections with other neurons and secrete dopamine. Another requirement is that researchers must determine the stage of stem cell differentiation (or specialization) that is most likely to produce a successful transplant in humans.
Stem cell transplants have successfully treated problems in rats that resemble those caused by Parkinson's disease. The big question is, will the transplants help humans who actually have Parkinson's disease? Hopefully, the answer to this question will soon be "Yes".
© 2014 Linda Crampton
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