Microbiological Causes Of Parkinson`s Disease

Microbiological causes of Parkinson`s Disease from a cellular perspective

Parkinson`s Disease is caused by the degeneration of dopaminergic neurons, and affects the automatic, central and enteric nervous system. Dopaminergic neurons are found in the substantia nigra pars compacta, meaning in two compact areas within the dark matter, a section of the brain high in neuromelanin and iron content. Dopaminergic neurons act as the main source of the neurotransmitter dopamine for the entire central nervous system in the mammalian brain/body and project mainly to the putamen, a large section of the brain that aids and prepares the movement of all mammalian limbs. Dopamine is an extremely important neurotransmitter, transmitted in both the central nervous system and peripheral system. In a healthy brain, a nigrostriatal pathway is composed of dopaminergic neurons which project directly to the basal ganglia and the striatal synapse. The electrical impulses that travel along the dopaminergic neurons originate from the SNpc. The Substantia Nigra, translated to black substance in latin, is a section of the brain that acts as a control centre of movement and reward. In a brain affected by Parkinson`s Disease, striatal dopamine deficiency takes place.

Striatal Dopamine deficiency is responsible for the major symptoms in PD and is a consequence of Neurodegeneration of the SNpc (Substantia nigra pars compacta) neurons. All patients with PD have a diseased nigrostriatal pathway, due to the degeneration of the pathway between the SNpc and the putamen. This degeneration is caused by a relatively large loss of dopaminergic neurons. In comparison, the nigrostriatal pathway between the SNpc and the caudate is much lower. The caudate`s main function is learning and the ability to store memory.

Neurodegeneration is caused by multiple failures within the brain mitochondrial dysfunction. Protein degradation, formation and stabilization of alpha synuclein and oxidative stress. Dopamine binds with the G protein receptor within the cell signalling pathway. Dopamine conversion has both a toxic and protective role, and whether it is toxic or protective depends on the cellular context of its role.

Causes of Neurodegeneration

Mitochondrial Dysfunction

Complex 1 is an electron transport chain that takes place in the mitochondria and is essential to the prevention of apoptosis in any living cell within the cell. A defect within complex 1 can cause oxidative stress and energy failure within the mitochondria. Oxidative phosphorylation takes place along this chain and is needed to produce ATP, which is essential for energy release in other parts of the cell. However, in patients with PD there is an abnormality of oxidative phosphorylation. This abnormality was found from the recognition that MPTP inhibits the electron transport chain, which leads to the inhibition of oxidative phosphorylation and complex 1. This defect within the mitochondria can be either genetic, with the possibility of a complex 1 defect being inherited in the genome of the mitochondria. On the other hand, systemic toxicity within the body and mitochondrial dysfunction can both be consequences of each other. The latter has been proven more likely with the knowledge that complex 1 inhibition caused by oxidative phosphorylation is not only found within the brain of PD patients, but includes other cells around the body, including platelet and cybrid cells of PD patients. If the inhibition of complex 1 were inherited, we can deduct that mitochondrial dysfunction should happen in many more areas of the body, since we know that the abnormal phosphorylation does not occur only in brain cells. However, more research is needed as mitochondrial dysfunctions are difficult to measure and therefore determine due to their very small nature. However, even if toxicity was found in other parts of the body not including the brain, we could still argue that since toxicity in the gut affects the vagus nerve, a nerve connected directly to the central nervous system, impulses are being transmitted across the entire system, and would therefore logically affect any area that is connected to the CNS.

ROS Superoxides

On a chemical level, the mitochondrial dysfunction mentioned in the previous section triggers a downward spiral once started, since the damaged mitochondria produces excessive amounts of superoxide radicals, specifically ROS superoxides. These radicals then begin a propagation reaction, attacking and breaking other molecules by homolytic fission. These superoxide radicals then create toxic hydroxyl radicals, creating a chain of increasing toxicity. These toxic molecules cause cellular damage and react with nucleic acids, lipids and proteins, causing massive disruption within the cell and increasing oxidative stress. Biological markers of oxidative stress are elevated in the SNpc of the PD brains, showing a clear correlation between oxidative stress, mitochondrial dysfunction and the progression of Parkinson`s Disease within a patient.

Likewise, ROS superoxide radicals are found to increase the amount of misfolded proteins. The body removes the excess of dysfunctional proteins by placing pressure on the ubiquitin- proteasome system, causing further excess stress.

Dopaminergic neurons are a friendly environment for ROS superoxide radicals, since the neurotransmitter dopamine produces many superoxide radicals and hydrogen peroxide, all of which react with the ROS superoxide. Furthermore when dopamine is oxidised DA-quisone is produced, a molecule which damages proteins and causes cysteines residues, adding to the chain of damaging reactions. The systolic concentration rises due to mitochondria-related energy failure, due to the disruption of vesicular storage of dopamine. This means that the oxidation of dopamine allows the rise of harmful reactions which damage intracellular reactions. This means that dopamine holds a crucial responsibility for rendering dopaminergic neurons in the SNpc to become exposed to oxidative attack and triggering a build up of toxic and damaging reactions. However at this stage data that convincingly links a primary abnormality of oxidative phosphorylation or ROS generation in PD has not been provided. This means that although we may be tempted to logically deduce this conclusion, we cannot assume without any well supported evidence.

Abnormal Protein Aggregation

The fourth and arguably most major cause of PD is the accumulation of misfolded proteins. This is because since most age related neurodegenerative diseases share the common feature of excess protein disposition we can deduce that protein aggregation is toxic for neurons. During protein folding, proteins change from a primary to tertiary structure. A primary structure is very simply a sequence of amino acids that form a polypeptide or protein. Several hundreds of these amino acids are linked to form a long chain. To become a tertiary protein the amino acid chain coils into a corkscrew shape called an alpha helix. This corkscrew shape is due to the hydrogen bonds formed between the oxygen atom on the end of a -CO- bond on the first amino acid and the hydrogen on the -NH- bond on the end of the fourth amino acid.

Beta pleated sheets are also a much more loose option when hydrogen bonding occurs along the amino acid.

For the secondary protein structure to change into a tertiary structure three more types of bonding need to occur. Firstly, as already discussed, hydrogen bonds form between any form of R group. This includes any strong polar groups, such as -NH-, -CO-, -OH- groups. Disulfide bonds also need to occur between the two sulfur-containing cysteine molecules. The disulfide bonds are strong covalent bonds and can only be broken using a reducing agent. Ionic bonds also occur between NH3+ and COO- groups. Due to the ionised nature of these bonds however, they can be easily broken by changing the pH of the environment. Lastly. Weal hydrophobic interactions hold non-polar R groups together/ The R groups tend to stay together mostly because they are repelled by the watery environment surrounding them. After this is complete the protein molecule becomes a compact structure resulting from the three dimensional coiling of the already folded chain of amino acids.

During this complicated process, mutations can cause the protein to fold incorrectly.The body reacts to misfolded proteins by introducing chaperones. In patients who suffer from PD (or suffer from an age related decline in health ) the chaperones do not properly target the cell. Polyubiquitination, a natural process, is overexpressed causing proteasomal degradation and causes misfolding in proteins, specifically -synuclein.

However, as we age, proteasomal dysfunction and chaperone activity is impaired, causing an excess in misfolded proteins which further inhibits the activity of the proteasome, which then is inhibited even more and so cannot degenerate the increasing excess of misfolded proteins which compromise the proteasome further. Protein aggregates are incredibly toxic and dangerous to the body, having potential to deform other cells or halt/ compromise the intracellular network in neurons. Toxic protein aggregations can also cause a cell to create cytoplasmic protein inclusions. Misfolded proteins do not directly cause apoptosis, but rather the active process of removing the proteins themselves. In inherited PD, pathogenic mutations are believed to be the cause of the disease, with the mutations causing abnormal protein conformations, or with mutations inherited in areas of other proteins responsible in recognizing/ processing misfolded proteins, which therefore allows build up of neurotoxicity to be left unchecked. On the other hand, research has not yet revealed the true cause that triggers dysfunctional protein metabolism. Some triggers include oxidative stress through damage caused by ROS superoxide radicals and through the oxidation of -synuclein, a protein that has a higher probability of aggregating when oxidatively modified. This oxidative modification is caused mainly by exposure to pesticides and herbicides, which initiate aggregation (and increase the probability of misfolding) of a-synuclein. However mutations in a synuclein add a genetic risk to the carrier of PD, as this forms an inherited form of PD. The fact that the body uses such massive measures, going as far as apoptosis, to get rid of any aggregated proteins, clearly shows us that misfolded proteins are neurotoxic and one of the major factors of dopaminergic neuron loss.