Generality
The reason why an individual falls ill with Parkinson's disease to date has not yet been fully clarified.
Numerous experiments have been conducted and following the results obtained it was concluded that the causes responsible for this pathology seem to be multiple.
Among the factors involved in the development of Parkinson's disease, the aspects concerning aging, genetics, the environment and exogenous toxins, but also viruses, endogenous factors, cellular damage, presence of high amounts of iron and finally apoptosis (programmed cell death process).
Aging
In Parkinson's disease, the biochemical process mainly responsible for clinical manifestations is the reduction of a neurotransmitter, dopamine, which is fundamental for the harmonious execution of movements. This neurotransmitter is normally produced by the pigmented cells of the black substance and it seems that the reduction of dopamine production is due to a massive degeneration of nigral neurons. However, it has also been shown that in the normal aging process there is a progressive degeneration of mesencephalic neurons. The meaning is that with advancing age, there is a physiological reduction of nigral neurons (400, 000 units at birth, a 25% reduction at the age of about 60 in normal healthy individuals).
These results allowed us to hypothesize that Parkinson's disease can be caused by an accelerated aging process. It is not yet clear, however, how this aging process so selectively affects only the pigmented nuclei of the trunk. It is plausible, therefore, that age can change the sensitivity of dopaminergic neurons to other factors responsible for the disease, such as exogenous acute insults (occasional toxic, environmental factor, viral agent) or endogenous, such as the catecholaminergic cytotoxic metabolism (which uses the so-called "catecholamines", which are adrenaline, noradrenaline and dopamine), particularly harmful for some neuronal populations and not for others that use the same neurotransmitter.
Genetics
Instead, by examining genetics, as far as Parkinson's disease is concerned, obviously there is great interest in trying to find out which gene is responsible for the majority of cases of illness. Between 1969 and 1983 studies were carried out by different groups of researchers on couples of homozygous twins. The results of this independent research have shown that genetic factors played a weak, if not very, role in the causes of Parkinson's disease. Based on these past studies, the hypothesis of a hereditary pathogenesis has been excluded for a long time. In recent years, however, some genealogies have been described in which the disease is transmitted in an autosomal way.
Exogenous environment and toxins
It has also been hypothesized that exposure to some exogenous agents may contribute to the development of Parkinson's disease. In fact, some studies conducted in the 1980s had observed that drug-addicted individuals who took synthetic heroin whose co-product was MPTP (1-methyl-4phenyl-1, 2, 3, 6tetrahydropyridine), developed a parkinsonian syndrome that showed lesions, both anatomically and pathologically, at the level of the black substance and which responded well to L-dopa. MPTP is neurotoxic, but in itself it would be harmless. Once introduced into the body, at the level of the central nervous system it is captured by cells which, through the activity of type B monoamine oxidases (MAO-B), metabolise it leading to the production of an active ion, 1methyl-4phenylpyridine or MPP +. Once produced, this ion accumulates inside the dopaminergic neurons, using the dopamine reuptake system. Once recaptured, it concentrates at the level of the mitochondria, where it acts as a selective inhibitor of the respiratory complex I (NADH CoQ1 reductase). Following this inhibition, there is a reduction in ATP production and consequently a decrease in efficiency of the Na + / Ca ++ proton pump. Subsequently there is an increase in the intracellular concentration of Ca ++ ions, an increase in oxidative stress due to the increase in the dispersion of electrons in the complex I and an increase in the production of superoxide ion by the mitochondria. The whole then leads to cell death.
The interest in this type of observation is very important because in addition to providing the possibility of producing experimental models of Parkinson's disease in the animal, it is known that many of the substances used in the agricultural sector, such as for example herbicides and pesticides such as Paraquat or Cyperquat, are composed of substances with structure similar to MPTP or to the MPP + ion.
In line with these observations, in fact, the epidemiological data revealed that those who use these substances, but not the consumers of products treated with these substances, get sick more easily than Parkinson's disease.
Following these observations, the line of thought was born that the cause of Parkinson's disease is directly linked to acute or chronic exposure to substances such as MPTP or similar, found in food, air and water or in other parts of the environment around us. According to this line of thinking, there is the environmental hypothesis, according to which, following various epidemiological researches conducted on healthy individuals and individuals affected by Parkinson's disease, it appeared that parkinsonians had been more exposed to substances such as herbicides or insecticides, or had carried out agricultural activities, had drunk well water or had spent most of their lives in rural areas in more numbers than healthy individuals, considered as a control group. However, recent studies have shown that the only real independent risk factor between parkinsonian individuals and healthy individuals is exposure to herbicides and pesticides.
Furthermore, among the various neurotoxins present, others have been identified as dangerous, including n-hexane and its metabolites, substances commonly found in glues, paints and gasoline . In fact, parkinsonian individuals who were exposed to hydrocarbons-solvents showed worse clinical characteristics than individuals suffering from Parkinson's disease who had perhaps led a better lifestyle. All this resulted in a worse response to the pharmacological treatments by the patients affected by the disease who had previously been exposed to hydrocarbons, and finally the result was a more serious and less manageable clinical picture.
It is important to remember that environmental toxins, including carbon monoxide, manganese, carbonic disulfide and cyanide ions, may be responsible for Parkinson's disease. In this case, however, these toxins have globus pallidus as the target organ, rather than the black substance.
Even the globus pallidus, however, is part of the basal ganglia, which will be discussed in later chapters.
Viruses and Infectious Agents
Besides the toxins described above, the hypothesis concerning the involvement of viruses as responsible for Parkinson's disease was not lacking either. In fact, in 1917, following the lethal epidemic of Von Economo, a large number of cases of Parkinson's disease had been found. However, following the non-determination of the virus and its disappearance in 1935, this hypothesis was no longer pursued. To date, no infectious agent has been shown to cause Parkinson's disease on either humans or animals.
Endogenous factors
Instead, more interest has been given to the hypothesis of endogenous factors . In particular, an important role seems to be played by oxidative stress or more simply "free radical pathology".
It is known that oxygen free radicals are characterized by an unpaired electron in the so-called external orbital. The radicals are highly unstable, reactive and cytotoxic formations. Our body produces free oxygen radicals as a result of normal cellular activities, such as: oxidative phosphorylation, purine basal catabolism, changes induced by inflammatory processes and also following catecholamine catabolism, including dopamine.
Oxygen free radicals include the superoxide anionic radical, hydroperoxyl, hydroxyl and singlet oxygen. The peroxidation of these radicals leads to the formation of hydrogen peroxide or hydrogen peroxide. The hydrogen peroxide is reactive towards organic substances, but it is able to interact with the transition metals (iron and copper) thus generating the most reactive hydroxyl radical. Following their formation, free radicals, due to their high instability, are able to bind to any part of every biological molecule. These molecules also include DNA, proteins and lipid membranes. Therefore, free radicals are also able to alter nucleic acids, to render structural and functional proteins inactive, and to deteriorate the permeability and pumping and transport mechanisms of membranes. In order to obviate the problem induced by free radicals, in physiological conditions, the cells present numerous systems, enzymatic and non enzymatic, capable of hindering the side effects of free radicals. However, when the balance between the defense mechanisms and the factors that promote the formation of free radicals is altered, the result is precisely oxidative stress.
One of the areas most susceptible to oxidative stress is represented by the central nervous system, due to the high oxygen consumption and the high content of oxidizable substrates (polyunsaturated fatty acids), metal ions (which increase radical reactions) and catecholamines . As described in the first part, neurons of the black substance or substantianigra are rich in dopamine. It should also be added that the antioxidant defenses of the brain are weak; in fact, there is a low concentration of glutathione (which has antioxidant properties) and vitamin E, plus there is almost no catalase (an enzyme belonging to the class of oxidoreductases, involved in the detoxification of the cell from reactive oxygen species) . Therefore, these toxic lesions can accelerate the progressive loss of dopaminergic neurons at the level of the nigra.
Despite the picture provided by the theory of free radicals, there are also other factors considered among the causes of Parkinson's disease. These include cell damage, which is based on a dysfunction at the level of the mitochondria, particularly at the level of the respiratory complex I. Indeed, some studies have shown that the activity of the respiratory chain in the brain of an individual with Parkinson showed a 37% reduction in complex I activity, leaving complex II, III and IV activities unaltered. Not only that, this selective reduction of the activity of complex I seems to be limited to the black substance and in particular to the pars compacta.
It has also been observed that in the black substance of parkinsonian individuals, there is a high presence of iron . Under physiological conditions, neuromelanin binds to nigral iron by sequestering it, while in patients with Parkinson's disease, nigral iron fails to be seized by neuromelanin. Free iron thus activates a series of reactions, such as the Fenton reaction responsible for the production of high levels of hydrogen peroxide, from which, as previously described, oxygen free radicals are formed.
Another important phenomenon that must be taken into account is the phenomenon of excitotoxicity . This is a hypothesis according to which excitatory amino acids released in excessive quantities would be able to induce neurodegeneration. The mechanism responsible for neurotoxic activity would be due to the binding of excitatory amino acids mainly to NMDA-type ionotropic receptors. The interaction between the substrate and the receptor stimulates the receptor itself, thus leading to an influx of Ca2 + ions within the cell. Subsequently these Ca2 + ions accumulate in the soluble fraction of the cytoplasm, consequently inducing the activation of calcium-dependent metabolic processes.
Apoptosis
Last but not least, the phenomenon of apoptosis or programmed cell death is also among the possible causes of Parkinson's disease. Apoptosis is a process, genetically programmed, and therefore physiological. In fact, the cells - based on the signals that come from the surrounding environment - are able to control apoptotic processes. The exposure of neurons to particular exogenous or endogenous mediators, can therefore influence the cellular control of apoptosis, inducing its activation and therefore causing neuronal death. It has recently been hypothesized that dopamine and / or its metabolites may play a role in the pathogenesis of Parkinson's disease because they would seem to be able to induce inadequate activation of programmed cell death.
