Diseases and Disorders

Peroxynitrite and Chaperonins in the Molecular Pathogenesis of Parkinson’s Disease

Aayush Setty


Abstract

Parkinson’s Disease is a common neurodegenerative motor disease, a neurodegenerative disease that affects normal movement, that is prevalent in the elder population. It is characterized by the selective neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta of the human brain. This disease is idiopathic, meaning its root causes are unknown and the mechanisms behind its molecular pathogenesis are not very well understood. As a result, treatments to the disease, such as Levodopa, mainly serve as symptomatic treatments or aim to slow down dopaminergic neuronal death. Over the years, there have been many proposals as to what fundamental molecular cascades lead to the development of selective neuronal death, but there has been no definitive mechanism outlined. Recent studies involving chaperone proteins and oxidative stress coupled with high throughput drosophila fruit fly studies have shed light on new possible molecular pathways leading to the pathogenesis of Parkinson’s Disease[1].

 

Apparent Pathology in Parkinson’s Disease

Although Parkinson’s Disease (PD) is idiopathic, the pathological markers of the disease are very well characterized. In contrast with other neurodegenerative diseases, neuronal loss in Parkinson’s is confined mainly to dopaminergic neurons in the substantia nigra pars compacta(SNpc), a structure located in the midbrain{2}. Dopaminergic neurons in the SNpc contain large amounts of neuromelanin, a dark polymer pigment similar to melanin, which gives a healthy substantia nigra a characteristic dark color[3]. In post-mortem analysis of Parkinson's patients, the SNpc was found to be devoid of the dark coloration that neuromelanin possesses suggesting the neuronal loss of dopaminergic neurons in the SNpc (Figure 1). 

Figure 1. Panel A shows a section of the midbrain from a control patient with a dark SNpc. Panel B shows a section of the midbrain from a patient that has PD and thus has a  light SNpc due to dopaminergic neuronal death. Adapted from Lima, et al (2012)[4]. 

On a cellular level, dopaminergic neurons in the SNpc of Parkinson’s patients show widespread accumulations of protein aggregates known as Lewy Bodies (LBs), which are mainly made of a relatively common soluble presynaptic protein called α-synuclein[5][6]. These aggregates form in two stages. First, they form soluble circular oligomers, otherwise known as protofibrils, and form insoluble fibrils in the second stage. These insoluble fibrils are thought to be the main constituents of LBs[7]. The role these LBs play in the pathogenesis of PD is unknown; although, some evidence cites it as being a neuroprotective mechanism, whereas other evidence shows it as a toxic structure [8]. 


Figure 2. LBs in the brainstem SNpc of PD patients are visualized through anti-synuclein antibody immunohistochemistry. These LBs are insoluble and mostly made of misfolded α-synuclein. Adapted from Baba, et al. ([9].

 

Pathophysiology of Parkinson's Disease

PD affects mostly the motor functions of patients. Symptoms such as the classic parkinsonian gait (short, shuffling steps resulting in a loss of balance), bradykinesia (slowed movement), and hand tremors serve as hallmark features in the diagnosis of PD [10]. The pathophysiology behind the development of these symptoms is well known and is isolated to one brain system: the basal ganglia. The basal ganglia and the cerebellum are important brain structures involved in the modulation of movement. The basal ganglia itself is very important in the proper initiation of movement and the proper regulation of voluntary movement. The SNpc is a crucial component of the basal ganglia system due to its role in supplying the circuit with the neurotransmitter dopamine. Dopamine itself is an excitatory neurotransmitter that serves as the primary means in which the basal ganglia initiates a movement [11].

In a properly functioning basal ganglia, the system will take in cortical inputs, process those inputs through two pathways,  the direct and indirect pathway, and ultimately ends with a thalamic output to the VA/VL nucleus. In a properly functioning basal ganglia, the processing segment of the circuit, as previously mentioned, has a direct and indirect pathway. The direct pathway promotes the initiation of movement, whereas the indirect pathway inhibits the initiation of movement. Thus, a balance between these two pathways leads to a comprehensive movement regulation system.  Dopamine supplied by the SNpc directly increases the activity of the direct pathway and inhibits the activity of the indirect pathway. The basal ganglia is able to have variability in the effects of dopamine due to the different receptors at the synapse of neurons in the direct versus the indirect pathway. The neurons in the direct pathway contain D1 dopamine receptors, which promote excitatory postsynaptic potentials (EPSPs) in the postsynaptic neurons and activate it. On the other hand, neurons in the indirect pathway contain D2 dopamine receptors, which promote inhibitory postsynaptic potentials (IPSPs) in the postsynaptic neurons and its activity[12]. 

Thus, the loss of dopaminergic neurons in the SNpc deprives the basal ganglia of dopamine, which is crucial in proper movement initiation. Without dopamine, the direct pathway would be under activated while the indirect pathway would be overactivated which results in difficulty of coordinated movements, bradykinesia, hand tremors, and shuffling gait. Patients have even reported that at late stages of PD they have to focus very hard on the movements they want to perform before their muscles actually perform that action. This symptom serves as a perfect example of how the pathophysiology of the disease in the basal ganglia leads to the manifestation of symptoms related to movement initiation. 

The activation of movement through the direct pathway is mediated through a system of disinhibition. In essence, as seen in Figure 3, the internal globus pallidus (GPi) and substantia nigra pars reticulata (SNr) send continuous inhibitive signals to the VA/VL nucleus of the thalamus. This, in turn, inhibits movement. The direct pathway inhibits the GPi and SNr with the purpose of deactivating the constant inhibition that it provides. By inhibiting the inhibition, the direct pathway allows for the initiation of movement. The indirect pathway sends excitatory signals to the GPi and SNr which magnify the inhibition that the GPi and SNr already enforce on the VA/VL nucleus[13]. This results in further inhibition of movement. 

Figure 3. The basal ganglia has two main pathways, the direct pathway and the indirect pathway. The excitatory signals (white arrows) and inhibitory signals (black arrows) are organized in a unique way for there to be an efficient pathway for movement initiation through the disinhibition of the thalamus through the direct pathway. Adapted from Bunner and Rebec (2016) [12].

 

Oxidative Stress in the Pathogenesis of Parkinson’s Disease

Mitochondrial dysfunction in many diseased states leads to the release of highly reactive free radicals and reactive oxygen species (ROS) into the cytoplasm. These free radicals and ROS tend to react with proteins and have the ability to change a protein’s primary, secondary, and tertiary structures, which can lead to widespread protein misfolding and aggregation or early proteolysis [14]. These free radicals and ROS pose no severe threat on their own due to the fact that cells possess cellular mechanisms to deactivate and dispose of ROS and free radicals with relative ease. Proteins such as superoxide dismutase (SOD) react with ROS and convert them into relatively harmless compounds. The cell is only put under oxidative stress (OS) if the cell’s internal anti-oxidant mechanisms are unable to reduce ROS concentration. This can either be due to an unusually high concentration of ROS and free radicals in the cytoplasm or if a cell’s protective mechanisms are degraded or are not functioning properly. In both scenarios,  ROS will ultimately interfere with the normal functioning of proteins, thus impeding the proper functioning of the cell.

Figure 4. A list of the effects of high concentrations of ROS may have on the different macromolecule classes in the cell. Adapted from Sharma, Jha, Dubey, and Pesssarkli (2012) [15].

Lewy bodies and α-synuclein aggregates have been long suspected to form as a result of OS in the SNpc dopaminergic neurons, however, the theory seemed unlikely due to the selective nature of neuronal loss in PD. This selectivity can most likely be explained through the finding that baseline ROS concentration in the SNpc is almost twice as much as other basal ganglia components, thus making the SNpc much more susceptible to OS than other structures [16]. 

It is widely accepted that OS plays a role in the progression of PD, but it is unclear if it is the direct cause or a later consequence of a larger cascade of molecular events. Regardless of the magnitude of the role that OS plays in PD progression, the presence of ROS, such as superoxide (O2-),  has been shown to lead to the formation of Lewy bodies and α-synuclein aggregates. Primate and mice models of PD have been induced with the use of pharmacological agents, such as MPTP and paraquat, to induce mitochondrial dysfunction, which leads to the production of free radicals [17][18]. These mitochondrial  complex 1 inhibitors effectively recreate the conditions seen in real PD patients due to the fact that in post-mortem analysis there is proof that patients had up to a 30% reduction of complex 1 activity and widespread oxidative damage [19][20]. 

Ultimately high levels of OS can trigger the activation of caspase 3 expression, which leads to apoptosis, programmed cell death.

 

Nitrative Toxicity

Mitochondrial dysfunction itself is solely responsible for the creation of more ROS, but not for cell death. The most common ROS created is superoxide, which is a byproduct of the electron transport chain in the mitochondria, but it is not toxic to the cell in most cases due to the presence of antioxidant proteins such as SOD and glutathione (GSH) [21][22]. However, when superoxide reacts with nitric oxide (NO), a common retrograde neurotransmitter, it forms a compound known as peroxynitrite (ONOO-). Peroxynitrite is a highly toxic reactive nitrogen species (RNS)  and can cause lipid peroxidation and protein nitration. Along with peroxynitrite, nitrogen dioxide (NO2) is also a powerful nitrative species[23].

In PD, ONOO- and NO2 in SNpc neurons have been suspected of causing widespread protein nitration and oxidative damage. Both have been shown to nitrate the tyrosine residues on proteins and free tyrosine in the cell. This, in turn, reduces their enzymatic activity, which could have widespread effects on countless molecular pathways. Nitrated tyrosine residues are known as nitrotyrosine molecules and are able to be stained for in PD models with LBs. It has been noted that nitrotyrosines are heavily present in the center of LBs which may mean that they are crucial in the initial formation of these LBs[24]. One protein that is particularly susceptible to tyrosine nitration is tyrosine hydroxylase (TH): a crucial enzyme in the formation of dopamine in SNpc dopaminergic neurons. Although this is the case, dopamine has been shown to prevent TH nitration outside the cellular environment. However, dopamine does not prevent a reduction in TH activity [25]. This is due to the fact that dopamine becomes the main target for oxidative damage by the nitrative species and oxidatively damaged dopamine molecules have been shown to decrease TH activity through cysteine modifications [26]. Thus eventually, there is a depletion of dopamine through the combined factors a reduction in the rate of dopamine formation and the constant oxidative damage to existing dopamine molecules. After this depletion, nitrative species are able to nitrate the tyrosine residues on TH molecules and form nitrotyrosine. 

In addition to this cascade, SOD has been shown to paradoxically catalyze the reaction between ONOO- and tyrosine residues to form nitrotyrosine [27]. Both this catalyzation and depletion of dopamine protection can lead to widespread tyrosine nitration and reduced TH activity and this reduces dopamine production. This reaction leaves SOD damaged and reduces its ability to dismutate O2-  into H2O2 [28].

Another factor that may lead to increased peroxynitrite concentration and toxicity is low uric acid levels. PD patients have decreased uric acid levels compared to controls. Uric acid is a powerful peroxynitrite scavenger and, thus, reduces peroxynitrite concentration. A reduction of uric acid in the body can lead to the unrestrained build up of peroxynitrite in cells [29].

Figure 5. The interactions between RNS, TH, and dopamine leads to a robust chain reaction that results in a reduction of dopamine production due to the nitration of tyrosine hydroxylase. Uric acid has been seen to scavenge for peroxynitrite, but PD patients have abnormally low levels of it. 

 

The Role of NO and radical - radical recombination

Although NO is crucial for peroxynitrite formation, excess nitric oxide (NO) is able to prevent the generation of excess nitrative radicals through radical - radical recombination reactions. NO is able to combine with both peroxynitrite ( ONOO-) and nitrogen dioxide (NO2) to form nitrogen trioxide (N2O3) which is a much less nitrative compound [30][31]. This validates another finding: PD patients have been shown to have a deficiency of tetrahydrobiopterin. A deficiency in this compound has the effects of increasing superoxide formation and decreasing NO formation from nitric oxide synthase, the enzyme that forms NO [32]. 

 

α-synuclein Aggregation and Lewy Body Formation as a Neuroprotective Process 

α-synuclein aggregate formation is a key feature in all PD cases and one of the hallmark markers of the disease. Although there is a strong general correlation between aggregate formation and cell death, it has not been formally concluded that the aggregates are a direct cause of cell death. Studies have shown that α-synuclein, in its normal form, may have a neuroprotective role and has been shown to protect neurons against OS-induced apoptosis [33]. The mechanisms and reasons for α-synuclein aggregation are largely unknown.

The specific presence of dopamine has been shown to increase the sensitivity of a cell to form α-synuclein plaques. The in vitro expression of excess α-synuclein in dopaminergic cells leads to quick apoptosis but no formation of α-synuclein plaques. In contrast, the same expression of α-synuclein in non-dopaminergic HCN cells had no signs of neurotoxicity or plaque formation [34]. This is most likely due to a lack of oxidatively damaged dopamine molecules in the HCN cells. The neurotoxicity seen in the dopaminergic cells were seen to be in response to soluble damaged α-synuclein products. The damaged α-synuclein did not form plaques but still caused apoptosis. Another study showed that the addition of normal dopamine to α-synuclein resulted in the inhibition of insoluble fibril formation, but resulted in toxic soluble protofibril accumulation. When antioxidants were added, the effects were relieved which suggests that dopamine oxidation was responsible [35]. In addition to this, post-mortem analyses of PD patients have found that cells with more plaques more often survive in comparison to cells that do not form plaques [36]. This supports the idea that plaque formation is actually a neuroprotective mechanism designed to sequester neurotoxic soluble α-synuclein products. 

Lipid peroxidation of polyunsaturated fats in the cell, a common effect of high levels of ROS and nitrative species, has also been shown to decrease oligomer and aggregate formation of toxic damaged α-synuclein. 4-hydroxy-2-nonenal, a product of lipid peroxidation, has been shown to prevent α-synuclein fibril formation and support toxic soluble α-synuclein [37][38]. 

 

Selective Apoptosis Through the Activation of the JNK pathway

Studies have shown that both patients with PD and animal models of PD have phosphorylated, and thus activated, Jun N-terminal Kinase (JNK) pathway proteins [39]. The JNK pathway, which is mediated by many factors in the cell, is responsible for many functions related to survival signaling and apoptosis. JNK-mediated apoptosis is carried out through the activation of the pro-apoptotic p53 protein which in turn activates caspase 3 proteins [40][41]. These caspase 3 proteins initiate apoptosis in any given cell. P53 knockout mice were shown not to have any neurotoxicity after being treated with MPTP, a common compound used to simulate PD, suggesting that the JNK pathway plays a major role in PD neurotoxicity [42]. 

The JNK apoptotic pathway is activated by a variety of cellular stressors, but in the context of PD, it has been shown to initiate apoptosis in the presence of excess ROS and oxidative damage to a cell [43]. Dopaminergic neurons in the SNpc seem to be at heightened risk of activation of the JNK pathway due to their baseline higher oxidative load than other dopaminergic neurons. In addition, oxidatively damaged dopamine compounds also show a possibility of directly influencing the activation of this pathway, but even more than this, its effects on α-synuclein show a greater role. Many studies have shown that α-synuclein plays a neuroprotective role not only against ROS, but also specifically in the context of the JNK pathway [44].  Thus, the dopamine-mediated formation of α-synuclein protofibrils not only decreases the neuroprotection that α-synuclein was once giving but also generates the toxic protofibrils. Not only do they pose risk through influencing the JNK pathway directly, but the generation of these protofibrils have been seen in correlation with Golgi fragmentation, which is an early stage of cell apoptosis and degeneration [45]. 

 

The Role of Chaperonins in the Pathogenesis of Parkinson’s Disease

Chaperonins are a class of proteins that catalyze the process of correctly folding a protein after translation or even after denaturation. The heat shock group of proteins have been seen to play a major role in the progression of neurotoxicity in PD models and have been seen in high concentrations in the SNpc cells of PD patients. A drosophila study of the effects of heat shock protein 70 (HSP70) on PD models observed that coexpression of HSP70 and α-synuclein lead to a decrease in neurotoxicity caused by the α-synuclein expression. Although this was the case, there was not a noticeable decrease in fibril and aggregate formation, but on the other hand, there was evidence that HSP70 became parts of the aggregate itself [46]. 

Other studies have shown that high concentrations of in vitro HSP70 concentrations have even been able to ameliorate α-synuclein aggregation. This amelioration of aggregate formation, although seen to be unnecessary for a reduction in neurotoxicity, has been seen to be a result of the preferential binding of HSP70 to prefibrillar protofibrils. In a controlled in vitro environment without proteasomes or lysosomes of any kind, these protofibrils stayed as soluble compounds and failed to form insoluble fibrils but paradoxically stayed cytotoxic [47]. Similar studies in vivo have shown, conversely, complete amelioration of the neurotoxicity associated with α-synuclein which leads to the suggestion that HSP70 is not solely responsible for the reduced neurotoxicity[48]. This leads to the suggestion that HSP70 allows other cellular mechanisms, such as proteasome systems, to process and destroy toxic α-synuclein protofibrils. 

HSP70 and HSP60 have also been shown to reduce RNS concentration, specifically peroxynitrite, in brain stem cells in the presence of a stressor. The chaperonins regulate NO production by interacting with NOS I and NOS II, the main producers of NO, to reduce NO production in the cells. The study showed that HSP70 and HSP60 were able to depress an OS mediated mitochondrial apoptotic cascade in brain stem cells through this decrease of NO concentration, which in turn reduced ONOO- concentrations which ultimately reduced OS [49]. Another study also showed that HSP70 was able to inhibit cell death by inhibiting the JNK pathway and eventual caspase-3 activation by reducing OS [50]. 

 

A Potential Pathway Describing the Molecular Pathogenesis of Parkinson’s Disease

All of these factors can be taken together to generate a potential molecular pathway to be used for further research to investigate the intricacies in the molecular pathway that governs PD pathogenesis. Although the initial stimulus for disease onset is unknown, the molecular cascade that occurs after it can be studied and understood with the eventual goal for better therapeutic targets. The pathway below contains all of the molecular mechanisms discussed in the article and proposes a partial pathway responsible for selective dopaminergic loss in the SNpc, α-synuclein aggregation, and various sources of neurotoxicity in PD.

Figure 6. A potential pathway for the molecular pathogenesis of Parkinson's Disease. Tetrahydrobiopterin and Uric Acid are marked as decreased with the red line next to them. The effects of both compounds have been marked as if they were in normal quantities, so their role in the pathogenesis of the PD is opposite to the effects shown because they are decreased.

 

Conclusion
PD is a highly complex disease with many different environmental and genetic factors that may go into its initiation in the human brain. Its selectivity to dopaminergic neurons in the SNpc makes it a very intriguing disease from a molecular pathology perspective. The limited ability to study the molecular mechanisms behind PD pathogenesis in human patients has been a major bottleneck in PD research but has been worked around through the generation of a variety of reliable animal models.  Drosophila and mouse models have made it possible to study PD on a much more specific level and will eventually allow for a very detailed outline of the molecular interactions that ultimately lead to dopaminergic cell death seen to cause Parkinsonian symptoms.

 


 

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    Aayush Setty

    Aayush Setty


    Aayush Setty is a freshman at Brown University as a part of the Program in Liberal Medical Education. He aspires to become an academic neurosurgeon working in the field of motor neurodegenerative diseases. He joined the IYNA as a board member after becoming a finalist at the USA National Brain Bee in 2018. Aayush loves to explore the outdoors: everything from rock climbing to hiking are some of his favorite past times. Outside of medicine, Aayush loves to explore the entrepreneurial process and hopes to use an education in economics and data science to help influence social and environmental policy.