What causes Parkinson’s disease?
After diagnosing a patient with diagnostic, a physician usually has a great challenge afterwards. This great challenge is answering a common question from the patient’s family. Why did this happen to him? This is a great challenge because the physician has to deal with explaining in simple terms a question without a definite answer. What causes Parkinson‘s disease? A question which has been tried to answer since 1817, year in which James Parkinson published his monograph “An essay on the Shaking Palsy”. For more than a century scientist only managed to describe what were the clinical manifestation and their underlying histopathological lesions.
Nevertheless, these findings were the basis for our current knowledge of the causes of Parkinson‘s disease. As the underlying histopathological lesion were discovered, theories and models of the pathogenic mechanism of the disease were made. Finally, through our understanding of the general pathogenic mechanism, several underlying causes have been proposed.
Therefore, in order to understand what causes Parkinson‘s disease, one must understand the histopathological lesion found in the disease. Also, it is essential to comprehend how the three general pathogenic mechanism, mitochondrial dysfunction, alterations of ubiquitin-proteasome system and phosphorylation variations, are caused by genetic, neurotoxic, infectious and traumatic factors. Finally, it is essential to recognize the complexity and interrelationship of the histopathological, pathogenic mechanism and underlying causes.
The first aspect that needs to be considered when discussing the causes of Parkinson‘s disease, is what are the histopathological lesions found in the disease. In other words, what defines the disease in its histopathology. The basic answer to this would be that in Parkinson’s disease, there is a progressive and irreversible process of degeneration and intracellular protein inclusions nervous tissue. Also, it is important to point the locations in which the neurodegenerative process occur. In Parkinson’s disease, the process is mainly found in the substancia nigra and the locus coeruleus. But the neurodegenerative process can also be found in the olfactory bulb, substancia nigra, raphe nuclei, dorsal nucleus of the vagus, and cortical areas. Another characteristic to consider is the content of intracellular protein inclusions (three proteins, alpha-synuclein, ubiquitin, and alpha B crystalline), which will be associated withthe three pathogenic mechanisms in Parkinson’s disease.
Having discussed the two main histological alterations in Parkinson’s disease and the location of these alterations, the next step is understanding the mechanisms that caused them. The three fundamental pathogenic mechanisms are mitochondrial dysfunction, alterations of ubiquitin-proteasome system and phosphorylation variations. Perhaps there are other pathogenic mechanisms, but currently, these are the best-understood ones at the moment. Also, they provide a relatively complete explanation of the process of developing Parkinson’s disease. It is important that these mechanisms are not the definite cause of the disease but rather the way in which the causes of Parkinson‘s disease hurt neuronal tissue and create the characteristic histopathologic lesions.
Also, it is import to remember the concept of homeostasis and how it relates to disease. Cells are in constant interaction with their surroundings and for this reason, they need to adapt to them. If they are not able to, they will be the target of diverse lesions. Cells have been equipped with the molecular mechanisms of dealing with these lesions. If these mechanisms are successful they will manage to maintain homeostasis. However, like in Parkinson’s disease, sometimes these mechanisms can be inactivated or oversaturated by lesions in the cell. As consequence, there will be further lesions in cells which can result in cellular death.
One of the basic mechanisms is mitochondrial dysfunction along with one of its major repercussions the formation of reactive oxygen species. As its well know, mitochondria are a type of essential organelles of great relevance with the energy supply of the cell. In particular, the electron transfer is in charge of generating ATP for the cell. Because of this complete mitochondrial dysfunction could result in incompatibility with life. However, in other, for there to be a neurodegenerative process akin to the one going on with Parkinson’s disease, the mitochondrial dysfunction needs to be progressive.
Progressive process resulting from mitochondrial dysfunction tend to be mediated by reactive oxygen species and reduced activity of the electron transport chain (resulting in deficient energy production.) The result of these leads to general cell malfunctioning. Deficient energy production can result in alteration of any physiological mechanism in the cell that requires the use of ATP or alternate energy-providing molecules. ATP-dependent mechanism varies from active transport in diverse cellular membranes to the activation of diverse signaling proteins.
Reactive oxygen species also have a great diversity of harmful effects on cellular function. Due to their chemical instability, reactive oxygen species can interact with almost any molecule in a cell. These interactions can result in mutations in the genetic material, degradation of lipids from the phospholipid bilayer (from which more reactive oxygen species are created) and, of great importance, in Parkinson’s disease protein structural changes. These protein structural changes, along with deficient energy production link mitochondrial dysfunction to another pathogenic mechanism, alterations of the ubiquitin-proteasome system.
The alterations of the ubiquitin-proteasome systems result in the dysfunction of another essential cellular process. The ubiquitin-proteasome system is responsible for the degradation of altered proteins. It does this through the addition of the ubiquitin peptides in proteins that signal the proteasome which proteins have to be eliminated. This is an essential process in cells because proteins alterations can accumulate and cause further lesions. In Parkinson’s disease, this is of great importance because one of the essential histopathological findings are intracellular protein accumulations. However, it is not known if protein accumulation is just a result of the degenerative process or an active mechanism of neuronal toxicity that causes neuronal degeneration.
Most evidence points to the latter; protein accumulation is an active mechanism of neuronal toxicity. First of all, protein accumulation could be a site of generation of more altered molecular components which in turn create more molecular alterations. Additionally, the accumulation of proteins could cause direct lesions of the integrity of the plasmatic membrane, resulting in leakage of essential components and introduction of harmful substances. Finally, these intracellular accumulations could interrupt with essential proteins, such as the phosphorylation enzymes involved in the third pathogenic mechanism of cellular injury.
The process of phosphorylation is essential in cellular function, particularly in signaling process. Phosphorylation or dephosphorylating have a great diverse of effects like the activation or deactivation of proteins. In Parkinson’s disease, variations in the phosphorylation process is one of the key pathogenic processes, in particular, kinase signaling process related to cell death. It has been theorized that there could be an activation of cellular death mechanism mediated through the mitogen-activating protein kinases and/or the phosphatidylinositol 3-kinases signaling pathways.
It also important to recognize the interaction of the other mechanism with phosphorylation variations in the cells. The phosphorylation process affecting cell death could also be affected my mitochondrial function. It is widely known that mitochondrial dysfunction has a direct association with cellular death through several molecules like the caspases and the BCL proteins. Also, it has been observed that several of the proteins found in intracellular accumulations, in Parkinson’s disease, are often hyperphosphorylated.
The mechanisms are the way in which the causes of Parkinson’s Disease create intracellular accumulations and neuronal cell death. A group of these causes are genetic alterations, which include the following genes SNCA, PARK, UCH-L1, DJ-1, PINK1, and LRRK2. All of these can cause neurodegeneration through any of the three pathogenic mechanisms. It is important to note that these mutations are not always an exclusive cause of Parkinson’s Disease and sometimes can be associated with other neurodegenerative diseases.
SNCA codes for one of the most important proteins involved in the pathogenicity of Parkinson’s syndrome. Regardless, that a patient doesn’t have a mutation in the SNCA gene, almost all causes of Parkinson’s Disease will interact with its product, alpha-synuclein. Alpha-synuclein is thought to have a function in intracellular trafficking of neurotransmitter, nevertheless, more research needs to be performed in other to prove this. The mutations of this gene include three types of point mutation (A53T, A30P, and E46K), and in rare cases gene duplications or triplications. The A53T and E46K mutations cause Parkinson’s disease with atypical features as such early onset of the disease or unusual psychiatric manifestations.
The alfa-synuclein protein is particularly important because it is the most common type of protein found accumulated in the neuronal cells of patients with Parkinson’s disease. As it was said before, alfa-synuclein tends to be hyperphosphorylated and found in protein structures called protofibrils and fibrils.
Another genetic alteration is found in the gene PARK which codes for the parkin protein. Parkin is an enzymatic protein involved in the ubiquitin-proteosome system. The mutations in PARK gene results in cells being unable to degrade proteins and the process of protein accumulations begin. UCH-L1 is gene that codes for another protein involved in protein degradation, ubiquitin carboxylase-terminal hydrolase L1. Its malfunction also results in protein intracellular accumulation.
The DJ-1 gene codes for a protein with unknown functions but it is theorized it is involved with mitochondrial function as an antioxidant, a reduction-oxidative sensor, a chaperon or protease. Studies have shown that in animal models, defects in this genes create oxidative stress sensitivity.
Genetic diseases also use the phosphorylation mechanism to create dysfunction. This is seen through the mutations in the LRRK2 and the PINK1 genes. The LRRK2 gene codes for a protein that sometimes is called dardarin. Dardarin’s functions are not currently understood but they are thought to be involved with phosphorylation and tends to be found in mitochondria. Also, it has been observed that dardarin sometimes interacts with parkin.
Finally, the PINK1 gene codes for PTEN-induced putative kinase-1. It is known that this protein is a mitochondrial kinase, however,the substrates are unknown. It has been observed that mutations in this protein result in mitochondrial dysfunction and accumulation of reactive oxygen species. The reactive oxygen species can result in mitochondrial DNA mutations and alteration of protein structures. One of the proteins altered is complex 1, which will be affected by certain neurotoxic causes of Parkinson’s disease. This will lead to further production of reactive oxygen species, intracellular protein accumulations, and cellular death signals.
Apart from the genetic causes of Parkinson’s disease, there are neurotoxic causes which mainly involve the mitochondrial dysfunction. (Once again, if the neurotoxic agents are the only cause of the symptoms this excludes the diagnosis of Parkinson’s disease. Parkinson’s disease is characterized by being a multifactorial illness.) These chemical agents include paraquat, 1-methyl-1-phenyl-1,2,3,6-tetrahidropiridine, and rotenone.
Paraquat the organophosphate group of chemical causes of Parkinson’s disease. Paraquat and its related chemicals cannot pass the brain-blood barrier, therefore it is theorized that its effects are the result of the creation of reactive oxygen species outside the nervous systems. In the other hand rotenone and 1-methyl-1-phenyl-1,2,3,6-tetrahidropiridine can cross the blood brain barrier and cause effects directly in the nerves cells. They also do this by creating reactive oxygen species but also they interact with the complex 1 of the electron transport chain. Meaning that apart from the lesions caused by the reactive oxygen species, they also cause deficient energy production.
Additionally, 1-methyl-1-phenyl-1,2,3,6-tetrahidropiridine interacts with BCL and caspases proteins. As previously stated these are mitochondrial proteins involved with the cell death signaling process originating from mitochondria’s.
Finally, there are theories about the chemical instability of dopamine. Perhaps due to this instability they can create reactive oxygen species and/or have intrinsic neurotoxic characteristics that result in neuronal lesions. This might also explain why dopaminergic cells, in particular, are susceptible to neurodegeneration.
The other two causes of Parkinson’s are actually considered risk factors by many because their pathogenic mechanisms have not been deciphered. Nevertheless, the association with Parkinson’s disease is hard to miss. This reminds us that there is a great of need for research in this disease. Even with only our current understanding of the causes of Parkinson’s disease, several therapeutical options are being developed. Many which are oriented to stop the pathogenic mechanism in Parkinson’s disease. Others seek to inhibit the causes of Parkinson’s disease from using the pathogenic mechanism and causing cell damage. Only through a greater understanding of the disease will scientist be successful in developing these technologies.