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The first time of Parkinson's disease was discovered in 1817. The discoverer was a British doctor, James Parkinson, he observed six patients who had shaking of their arms, legs and body involuntarily and published all these cases on the book, Essay on the Shaking Palsy. The disease was suggested named as Parkinson's disease by a French neurologist, Charcot, later. (1)Until now, we know that the Parkinson's disease (PD) is a progressive neurodegenerative disorder that is died of specific group of neurons inside the middle of the brain, which is loss of the dopaminergic neurons in the substantia ngira compacta (SNc) collecting to the basal ganglia. These neurons contain a chemical called dopamine. PD is the most common and primary form of Parkinsonism, and the major symptoms of this disease are tremor, rigidity, bradykinesia and postural instability.(2-3) In recent researches, the cause of PD is still unknown. However, scientists think that the pathogenesis of this disease is complex, involving the multi-factors to occur to cause the person who get this disease. (12) They are strongly evidence to believe that the cause of PD are related to the development of cytoplasmic aggregates known as Lewy bodies, the mitochondrial dysfunction and the oxidative stress. These kinds of mechanism cause the dopaminergic neurons degeneration, further to cause the Parkinson's disease.
Dopamine is the catecholamine neurotransmitter that release from the dopaminergic neurons that located at the substantia ngira compacta (SNc) of the brain (2) (Fig. 1). The functions of dopamine are controlling of the movement, emotional response, the feeling of pleasure and pain, etc. in the normal brain of the person, there are contained around 400,000 of dopaminergic neurons (2) in the SNc.
Fig. 1 (7)
In the general mechanism of dopamine, when the action potential is reached to the presynaptic terminal of the dopaminergic neurons, the tyrosine (Tyr) will be generated to be dihydroxyphenylalanine (DOPA) which is catalyzed by the tyrosine hydroxylase, then it converted to form the dopamine, which is catalyzed by the DOPA decarboxylase, and the carbon dioxide is removed from the DOPA. The transmitter dopamines are carrying by the vesicles. The action potential depolarized to cause the Calcium ion channel opening, leading to the release of the vesicles with dopamine from the presympnatic membrane. The neurotransmitters carry out the nerve impulse across the presympnatic membrane to the synaptic cleft. The dopamine are bind to the dopamine receptors on the postsympnatic membrane which is located at the corpus striation of the basal ganglia, that is the G-protein coupled receptors, and it is the nigrostriatal dopamine system(5). The excess neurotransmitter will be reuptake back to the presympnatic terminal, then degraded and recycled by the enzyme called monoamine oxidase (MAO). The dopamine bound to the dopamine receptors, causing the conformation changes of the receptors and providing the binding site for the G-protein. The G-protein binds to the dopamine receptor inside the postsympnatic terminal. The G-protein binding to the receptor induces the conformation changes in the G¡€ subunit of G-protein, and then the GTP-GDP replacement will be caused. The GTP will replaced the GDP of the G-protein that the G-protein can said to be activated. The GTP-linked G¡€ subunits will dissociated with the G¢ complex, and bind to the effecter enzyme known as adenylate cyclase (AC). The AC generates the ATP to be cyclic AMP (cAMP) which is the second messenger; it uses to activate the protein kinase A (PKA). The activated PKA will phosphorylates other proteins, causing the opening of the ion channel and produced the effects. After that the dopamine will be unbind to the receptor, and the GTP is hydrolyzed to GDP by the GTPase activity of the G¡€ subunits. The G¡€ subunits will dissociate with the AC and re-associate to the G¢ complex, now the receptor will be return to the resting status. There is the general pathways of the dopamine, and we know that the action can be excitatory and inhibitory the body function in the result. Now we know that the dopamine receptors can be separated to D1 family and D2 family.(6) totally we found five types of dopamine receptors in the corpus striation of the basal ganglia. They include different effect to be generated finally, including the skeletal movements control.
Dopaminegic neurons degeneration
As we mentioned, the dopamine is the neurotransmitter which produced by the dopaminergic neurons in the SNc. The dopamine not only can be converted to the norepinephrine and epinephrine, but also can be work as the neurotransmitter by itself (Carlsson, 2000)(7), to produce smooth, purposeful skeletal muscle activity. Therefore, the large mass of the dopaminergic neurons are died, causing the loss of dopamine generation. Whereas loss of dopamine causes the nerve cells of the corpus striation to fire out of control, then the patients cannot control their muscle activities normally. Hence the symptoms of tremor, rigidity, bradykinesia and postural instability will be occurred, that will be diagnose as the Parkinson's disease. Based on the research, most of PD's patients are loss of 80% or more dopaminegic neurons and the reasons are not confirmed.
Lewy Bodies, Mitochondrial dysfunction and Oxidative stress with cell death
We found that the presence of Lewy bodies in the dopamiergic neurons in the SNc from the diagnosed PD's patients. The Lewy body is an abnormal aggregate of protein that can be found in the nerve cells from Alzheimer's disease patients and the PD's patients, and it is made by the ¡-synuclein and ubiquitin ligase. The ubiquition ligase is an enzyme for the breaking down of the abnormally large protein. Based on the recent researches, normally, the ¡-synuclein may locate at the presympnatic nerve terminal, and serves as a molecular chaperone, may be function in the protein modification and trafficking. (8) The actual function of ¡-synuclein still not be ensure. But the researchers believe that the mutation of the ¡-synuclein may lead to misfolding and clumping of the proteins, causing the dopaminegic neurons death. Moreover, we still do not know that the Lewy bodies whether cause of the cell death.
Another theory of causes of the dopamine cell death is the oxidative stress which made by the excess amount of free radicals. Free radicals can be the molecules or ions that presence in our body, that they attach themselves to other cells or membrane, and breakdown the molecule, causing the injury of the cells' proteins, lipid and DNA, finally causes the cell death. Therefore, it will increase the oxidative stress while the cell death and becomes fragmented. In recent researches, we know that the breaking down of the dopaminergic neurons, some molecules are formed such as peroxide, which form with iron to be the toxic free radicals. This kind of free radical can be detoxified by the glutathione.(2) When the free radicals are excess produced, and not enough of glutathione are provided, it will cause the oxidative stress and damage of the cells, triggering the apoptosis of the cell.
In the recent researches, we are strongly evidence to believe that the mitochondrial dysfunction have association to the degeneration of the dopamine cell. The mitochondria are the ATP production centre and are susceptible to oxidative damage. As we know when the DNA of the cells has been damaged, the cell death signals, the p53 proteins, activate the pro-apoptotic protein known as Bax/Bak (12), accumulating in the outer membrane of mitochondria. The Bax causes the mitochondria to release Cytochrome c, which will form with Apaf-1 and interact with the procaspase-9, and the ATP to trigger the gathering of the apoptosome. The apoptosome activates the caspase-9, further to activate the caspase-3; they cleave the protein and activate the apoptosis to cause the cell death. Based on several researches, the mitochonda dysfunction due to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropridine (MPTP), which is by-product of heroin. The MPTP will be metabolize to MPP+ in the body, which enter the mitochondria and inhibit NADH and infer mitochondria complex I (CoQ10). The inhibited NADH will block the production of ATP in the mitochondria, ATP is the essential energy for the functioning of the cells. Therefore, it will cause the dopaminergic neuron death. Furthermore, CoQ10 is an antioxidant for preventing the free radicals binding, so called ubiquinone that we have been mentioned. MPP, will infer the activity of CoQ10, causing the free radicals bind to the cells and damage the DNA, further causing the apoptosis and oxidative stress. The researchers have been showed that around 40% of CoQ10 activity decreasing in the SNc of the PD's patients. Hence, the mitochondrial dysfunction always gathers with oxidative stress, and link with PD.
We can concluded that the Parkinson's disease is causes by the degeneration of the dopaminergic neurons. This kind of neurons provide the important function in controlling muscle movement. Although we still know limit in the neurons degeneration, we have got the strongly evidence to believe there is associated with the interaneuronal protein protein aggregates known as Lewy body, the mitochondrial dysfunction and oxidative stress. For the future studies, we will mostly focus on the genetic level, to know more about the Lewy Bodies, especially ¡-synuclein. Since more and more researches showed there is some gene mutation inside ¡-synuclein. In addition, we believe that the gene mutation have happened in the mitochondrial DNA, and cause the mitochondrial dysfunction, triggering the oxidative stress. Therefore, the genetic level will be helpful to know about the core of the dopamiergic neurons degeneration, further to the PD and the PD treatment developing.