A brief history
What do Muhammad Ali, Michael J. Fox, Pierre Trudeau and Mao Tse Tung all have in common?
They are, or have been, public faces of a debilitating disorder known as Parkinson’s disease (or “PD”). PD affects millions of people worldwide and is present in about 1% of the total global population, with an increase in prevalence (2-3%) in those above 50-70 years of age. It equally affects people from different ethnicities and socio-economic status, but it is more common in men than in women (Samii 2004)
The first scientist to formally describe the disease was the British physician James Parkinson, who in 1817 wrote a famous essay on “The Shaking Palsy”. In his work, he described the daily lives and symptoms of six patients affected by problems such as constant shaking, rigidity and slowness of movement. Later in the 19th century, the disease was formally named after Dr. Parkinson by the French neurologist Charcot. Interestingly, the characteristics of the disorder had been described as early as in the second century AD by the Greek physician Galen, and reference to symptoms that resemble those of PD can be found in the Bible as well as in ancient Indian and Egyptian texts (Garcia Ruiz 2004).
Today, much more is known about the physiological basis for the disease, with promising therapies emerging, but we are still far from understanding what causes it and how to ultimately cure it.
What is the physiological basis for Parkinson’s disease?
PD is diagnosed when resting tremor, rigidity, slowness of movement and gait disturbance are present. Other commonly found symptoms include a rigid “mask-like” facial appearance, as well as speech and cognitive problems.
These symptoms are thought to result from the loss of neurons in a region of the brain called the substantia nigra (latin for “dark substance”). Generally, symptoms become manifest when about 80% of the neurons have been lost. These neurons send their projections to a region of the brain that has a very important role in motor control, the striatum. The latter is part of the basal ganglia, a complex array of neuronal circuits that are ultimately responsible for the initiation and control of movement that occurs through exchange of information with the motor cortex (Purves 2004).
Neurons in the substantia nigra communicate with those in the striatum through a chemical messenger called dopamine. Dopamine has a two-fold action on the neurons of the striatum. Its release acts on a neuronal circuit that is normally responsible for the excitation of movement (the direct pathway), as well as on a circuit that normally inhibits movement (the indirect pathway). By stimulating two different types of chemical receptors found on striatal neurons, dopamine excites the direct pathway and inhibits the indirect pathway, ultimately inducing the motor cortex to promote movement (Purves 2004).
In PD, the lack of dopamine results in the overall suppression of movement: the inhibitory action of indirect pathway is left “unchecked” and the excitatory effects associated with the direct pathway are diminished. Therefore, the initiation and control of movement are made difficult, and “freezing” can occur during walking, reaching for an object, or other common everyday actions.
The “Frozen Addicts”
Nobody knows with certainty what causes PD, but a few theories have emerged. As often happens in Science, clues regarding a particular scientific “mystery” are often discovered by mere accident. In the case of PD, this occurred in 1976, due to the mistake made by Barry Kidston, a young chemistry grad student in Maryland. Barry was trying to manufacture MPPP, an illegal synthetic opioid, when a small error in his procedure led instead to the production of the toxin MPTP.
Unaware, Barry injected himself with the drug, and within a few days he quickly developed symptoms of PD. As well, in 1982, seven drug addicts in the Santa Clara County, California, became “frozen” in a PD-like state practically overnight (Schwarcz 2005). It was established that MPTP had been present in a contaminated batch of synthetic heroin used by the addicts. Analyses later conducted on monkeys, as well as an autopsy performed on Barry Kidston (who died a few years later of cocaine overdose) showed that MPTP targets and kills neurons in the substantia nigra specifically.
Studies have shown that once taken up in the brain, MPTP is metabolized into the neurotoxin MPP+, which induces degeneration of the important cellular organelle, the mitochondria (Samii 2004). MPP+ is thought to have a high chemical affinity for the dark pigment that gives the substantia nigra its characteristic colour. That is, MPP+ could selectively target these neurons, thus partially explaining the pattern of neuronal death observed as a result of MPTP use. (Rosenzweig 2005).
Today, it is thought that prolonged exposure to toxic chemicals found in pesticides, herbicides or urban water wells in industrial areas could be linked to the development of the disease, as these chemicals might contain toxins that have a similar mode of action to MPTP and its derivative MPP+ (Samii 2004).
Although most of the symptoms found in MPTP-induced parkinsonism are the same as in idiopathic PD (a fancy term used to indicate the fact that the actual causes of the disease are unknown), it should be noted that there are some important differences between these two variants. The main one is that MPTP induces a very rapid degeneration of neuronal cells, while the cell death normally occurring in the disease is a slow process that can take decades.
Moreover, abnormal protein clumps called Lewy bodies (which interestingly are also found in some forms of Alzheimer’s disease) are often present in the brains of patients with Parkinson’s, but have not been found in cases of MPTP-induced parkinsonism (Fukuda 2001). Therefore, MPTP-induced neuronal death can be studied for possible clues on the mechanisms behind development of the disease, but much is still to be explored. Nevertheless, the discovery of MPTP has greatly advanced research on the disease, as the toxin is now used to induce parkinsonism in animal studies for the subsequent testing of new drugs treatments or other therapies.
The “Italian connection” and other genetic clues
Although environmental factors, such as the effect of toxins, or even of viruses (Ogata 2003), are thought to play an important role in the development of PD, several clues point to genetic culprits as well. For example, evidence for the genetic transmission of the disease has been found in a large Italian family where PD seems to occur when a defective copy of the gene PARK1 is inherited (Polymeropoulos 1997). The gene is thought to be linked with the production of one of the proteins that form Lewy bodies.
Similarly, other studies point to genes that are involved in the processes of ubiquitination. and protein degradation (Samii 2004). When proteins inside a cell are defective or otherwise damaged, they are tagged with a molecule called ubiquitin. This tagging process allows defective proteins to be later recognized by specific molecular players in the cell, and selectively destroyed. If the tagging process is ineffective, abnormal proteins can accumulate inside a cell, leading to cell death. It is thought that abnormal copies of genes responsible for one or more steps in the protein degradation pathway could be the culprits for the neuronal degeneration seen in PD. That is, damaged proteins could somehow accumulate in the neurons over time, leading to progressive cell death. However, it is still not clear why only cells found in the substantia nigra would be affected.
Available therapies: L-dopa
Since its discovery in the 1960’s, the best available therapy for PD has been the use of the chemical L-dopa. This is basically a precursor of dopamine, which is normally lacking in PD. Dopamine cannot be directly used in PD patients as once administrated, its structure does not allow it to enter the brain. When a drug is administered orally, it enters the bloodstream, through which it eventually reaches the brain. However, the passage from the bloodstream to the brain cells happens through a structure called the blood-brain-barrier, which has a protective function, and generally does not allow large chemicals to pass through (you can imagine it as being like a sort of molecular sieve). Dopamine cannot cross through, but, fortunately for PD patients, L-dopa can. When it reaches the brain, it is converted to dopamine through a chemical reaction. In the brain, dopamine can then reduce the symptoms of PD by temporarily restoring the correct stimulation pattern of neurons in the striatum. (Rosenzweig 2005).
Although L-dopa reduces PD symptoms, there are several issues associated with its use. For example, it is found that the drug is more effective when used in the first stages of the disease, as after 5-10 years of continuous use a large number of patients (50-80%) develop side effects such as the occurrence of involuntary movements and other motor fluctuations (Samii 2004). Another common problem in L-dopa users is the recurrence of tremor, rigidity and freezing in an “on-off” pattern. This pattern is thought to be related to the time that it takes for L-dopa to reach the brain and be effectively transformed into dopamine.
The chemical step that converts L-dopa to dopamine is in fact quite rapid (in technical terms, L-dopa has a short “half-life”), while it takes longer for the drug to be absorbed in the bloodstream and consequently reach the brain cells. The result is that the positive effect felt by the patients is quite short, as most of the L-dopa that reaches the brain is quickly converted into dopamine and “used-up” before another drug dose can newly reach the brain. This pulsatile stimulation pattern thus leads to on and off recurrence of symptoms. Controlled-release versions of the drug have been developed, but it is still not known with certainty whether their use will result in the development of other kinds of side effects (Flores 2004).
Other available therapies
Drug administration is not the only available therapy for PD patients: other forms of treatment include surgery, electrical deep brain stimulation (DBS) and more recently, cell transplantation.
Surgical intervention was introduced as a form of treatment in the 1940’s and 1950’s, and later abandoned in the 1960’s with the discovery of L-dopa. Since the long-term use of the drug has proven to have several side effects, the use of surgery has become newly popular. (Samii 2004). Surgery consists in the physical removal or destruction of parts of the basal ganglia that are responsible for the tonic inhibition of the motor cortex that is left “unchecked” when dopamine is no longer released on striatal nerve terminals.
Although surgery can reduce motor symptoms, there are a lot of problems associated with it. Besides the risks linked to the surgical procedure itself, cognitive deficits are a very common side effect, as are motor fluctuations, confusion, limb weakness, difficulty in swallowing and loss of vocal ability. In the brain, it appears that “no man is an island” (in the sense that neurons are highly interconnected with each other), and although neurologists may have mapped the brain into distinct regions for ease of modeling, no such boundaries exist in the physical sense. Surgery or removal of certain areas can thus affect neuronal pathways other than the ones of strict interest, with the result of creating permanent damage. For this reason, surgery is now used only in extreme cases of PD that have not responded to L-dopa therapy (Samii 2004).
A more recent alternative to surgery is deep brain stimulation, or DBS. This consists of the physical stimulation of the same brain areas that are usually removed during surgery. Electrodes are implanted in the brain, and high frequency stimuli are applied, a procedure that is found to mimic the physical removal of the areas of interest. However, because the stimulation is only temporary, DBS is associated with fewer irreversible traumas as compared to surgery, and it is found to effectively reduce symptoms such as slowness of movement, rigidity and gait problems. Unfortunately, side effects such as motor fluctuations, seizures, brain hemorrhage and cognitive problems can still arise. In some patients, unusual sensory symptoms like tingling, burning and prickling also occur, as well as speech disturbances. (Samii 2004)
Recent research has also been directed at creating a way to continuously supply dopamine into the brain, thus bypassing some of the problems associated with other therapies. Theoretically, this could be done by implanting dopamine-producing cells directly into the striatum. Practically, this is not as simple as it might sound. Common problems associated with transplantation are an immune reaction and consequent destruction of the foreign implanted tissue, as well as the development of motor fluctuations. For example, fetal cells originating from the substantia nigra have been tested, and although they have a good survival rate in patients, they seem to induce development of severe motor side effects. Moreover, ethical issues are associated with the use of cells of fetal origin: in the case of fetal nigral transplantation, several donors (4-8) are needed for the therapy to have an effect (Flores 2004).
Another candidate for transplantation that has recently been used with positive results is human retinal pigment epithelial (hRPE) cell tissue. HRPE cells are found in the retina of the eye, where their role is to supply nutrients to other cells and remove cellular debris. (Flores 2004). More importantly, these cells also produce L-dopa. Promising results have been obtained in animal testing (rats, monkeys) of the therapy, and a preliminary study in the United States has shown good improvements –with few side effects- in 6 PD patients that were implanted with hRPE cells for 2 years (Flores 2004).
However, as hRPE cells are non-neuronal, there is little data concerning their exact mode of action in a neuronal environment, and not much is known about their long-term level of survival. That is, how long can they really be effective for? Are the observed positive effects associated simply with L-dopa release or do other kinds of chemical and molecular interactions occur between the implant and the striatum? Studies are currently performed to try and answer some of this questions, but much is still to be investigated before hRPE cell transplantation can be routinely used an effective therapy.
Will the mystery be solved within this century?
Our knowledge regarding Parkinson’s disease has come a long way since the days of the “Shaking Palsy”. However, it is clear that much research needs to be done before the causes of the disease are fully understood and an effective therapy is established.
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