Paraoxonase Role in Human Neurodegenerative Diseases Part 1

Abstract: 

The human body has biological redox systems capable of preventing or mitigating the damage caused by increased oxidative stress throughout life. One of them is the paraoxonase (PON) enzymes. 

Biological oxidation is a chemical reaction that plays a very important role in our bodies. It helps us convert nutrients in food into energy and maintains the normal structure and function of the body. However, biological oxidation is not only beneficial to the body but is also closely related to human cognitive abilities.

Research on oxidation shows that it also occurs in our brains. Although oxidation itself is not a good thing, proper oxidation plays a very important role in improving human memory and cognitive function. Some studies show that people with proper oxygenation perform better than those with improper or excessive oxygenation.

So, how do we ensure our bodies are getting proper oxygenation? It's not difficult. First, we need to ensure a normal and healthy diet and lifestyle. We need to consume enough vitamins and minerals and avoid smoking and excessive alcohol consumption. Additionally, exercise is a great way to increase your oxidation levels. Proper physical activity and exercise can help us maintain healthy oxidation levels by increasing the body's utilization of oxygen.

In short, biological oxidation is closely related to human cognitive ability and memory. While oxidation itself is not a good thing, proper oxidation can help us improve memory, cognition, and intelligence. We can ensure that our bodies get enough oxygen through a healthy diet, lifestyle, and proper exercise. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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The PONs genetic cluster is made up of three members (PON1, PON2, PON3) that share a structural homology, located adjacent to chromosome seven. The most studied enzyme is PON1, which is associated with high-density lipoprotein (HDL), having paraoxonase, arylesterase, and lactonase activities. 

Due to these characteristics, the enzyme PON1 has been associated with the development of neurodegenerative diseases. Here we update the knowledge about the association of PON enzymes and their polymorphisms and the development of multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD).

Keywords: paraoxonases; oxidative stress; multiple sclerosis; amyotrophic lateral sclerosis; Alzheimer's disease; Parkinson's disease.

1. Introduction

Over the years, biotechnological changes and advances have guaranteed the population a significant increase in life expectancy that does not necessarily involve an increase in quality of life and/or having a healthy old age. 

The human body is a complex organism that maintains a balance of essential biochemical–physiological functions. When this balance is broken, the human body acts to restore homeostasis. However, in certain situations, this is not possible, and as a biological characteristic damaged tissue is observed to be accompanied by loss of function and cell death. Such events can occur in any part of the human body: Cutaneous, skeletal, muscular, cardiovascular, respiratory, digestive, urinary, genital, and nervous systems. 

When irreparable damage is observed in the nervous system, the neurodegeneration process is established. The signs and symptoms are noticeable in the short to long term, depending on the location in the central nervous system (CNS) where the damage has started. Aging is considered a risk factor for the onset of the degenerative process. For instance, currently, around 50 million people live with dementia, and it is expected that by the year 2050, this number will triple (approximately 152 million people) [1,2]. The etiology of several neurodegenerative diseases is still unclear, being multifactorial [3,4]. 

First, there are different neurodegenerative diseases, since the CNS is composed of different cell populations, in different areas, with highly specialized and unique functions. However, some risk factors are common among these diseases, such as Exposure to certain toxins; presence of certain polymorphisms; changes in cholesterol metabolism; decreased antioxidant activity, and increased oxidative stress. 

All of these factors together favor the loss of function and death of nerve cells [5–8]. The transport of human cholesterol is complex and joint integration between lipoproteins, enzymes, and apolipoproteins (Apo) is necessary, Figure 1. Free cholesterol can be easily oxidized by reactive oxygen species (ROS), giving rise to a group of compounds called oxysterols. 

Oxysterols participate in several pathophysiological processes such as drug resistance, stem cell differentiation, cell proliferation, and death [9–16]. They are also inducers of neuroinflammation and have a role in neurodegenerative diseases [17,18].

Another factor associated with neurodegenerative diseases is the increase in oxidative stress in the CNS. Oxidative processes of cellular metabolism lead to the formation of reactive oxygen or nitrogen species (RNS), due to the partial reduction in molecular oxygen (O2) by both free electrons and radicals [19,20]. 

The primary ROS products generated after the partial reduction of O2 are singlet oxygen (1O2), O2 •−, and H2O2, while subsequent reactions generate hydroxyl radical (OH•) and hypochlorous acid (HOCl) [19,20]. ROS and free radicals induce progressive damage to macromolecules such as DNA, lipids, carbohydrates, and proteins [21,22]. Increased ROS interfere with cell signaling, leading to several metabolic changes, including modification in the permeability and fluidity of phospholipid membranes. In addition, the active and passive transport of compounds and substrates through membrane cells is also affected [21,22].

The human body has many enzymatic systems for the protection of genotoxic damage, such as cytochrome P450, and directly or indirectly through free radical scavenging, such as paraoxonase (PON) [21]. Paraoxonases protect HDL and LDL from oxidative stress by removing ROS produced by the metabolism [23]. Here, we present the main evidence described in humans linking paraoxonase enzymes to some of the most frequent neurodegenerative diseases, discussing possible mechanisms of action.

2. Paraoxonase Family

The paraoxonases family consists of three enzymes: Paraoxonase 1 (PON1), paraoxonase 2 (PON2), and paraoxonase 3 (PON3), all having antioxidant and hydrolase activities. Although PON enzymes are widely distributed throughout the human body, these enzymes are mainly synthesized in the liver. They are present in different tissues and are mainly associated with cell membranes and some lipoproteins, although free enzyme was described in the blood. 

Historically, paraoxonase was named after its ability to hydrolyze paraoxon, a compound of the organophosphate insecticides class, to the metabolite p-nitrophenol [24]. In vivo, paraoxon, the most toxic form, is an oxidized product of biotransformation of parathion [24]. 

The PON family can metabolize other compounds such as Plucuronide drugs, lactone compounds, aryl esters, aromatic carboxylic acid and unsaturated aliphatic esters, cyclic carbonate, nerve gases, and some carbamate insecticide classes. Figure 2. Furthermore, PON inactivates lipoxidation derivatives of low-density lipoprotein (LDL) [25–27].

2.1. Paraoxonase 1 (PON1)

Paraoxonase 1 is a calcium-dependent glycoprotein of 354 amino acids, with a molecular weight of 43-47kDa. In humans, PON1 is encoded in chromosome seven (7q213–221), synthesized mostly in the liver, and in small quantities in the small intestine and kidneys [30,31]. PON1 was first identified in mammals during the 1950s [32]. It has been found in other animals, although its activity is reduced [32–35].

PON1 is anchored in the HDL3 fraction of high-density lipoproteins (HDL) in plasma [36]. The esterase activity of PON1 comprises the lactonase, homocysteine-thiolactone (HTase), and arylesterase (AREase) activities [36]. 

The binding of PON1 to HDL in the bloodstream keeps all PON1 enzyme activities stable, Figure 3. Although most of the circulating PON1 is found in HDL, it can also be found in very low-density lipoprotein (VLDL) and postprandial chylomicrons [37]. PON1 can be transferred from HDL to VLDL and to circulating cells such as endothelial cells and macrophages that are in contact with HDL [31]. 

This enzyme maintains its end-N signal sequence, which is a hydrophobic part that binds the enzyme to HDL. The enzyme has two calcium-binding sites: One for enzyme stability and the other essential for enzymatic hydrolytic activity. Selective chemical modification of aspartic acid (D) and glutamic acid (E) residues with carbodiimides prevents Ca2+ binding and inactivates human PON1. It has three residual cysteines, in positions 353, 42, and 284. 

The first and second of these residues form a disulfide bridge through cysteine 284, participate in orientating PON1 or bind it to its substrate (6), and appear to be essential for the protective effect of PON1 against LDL oxidation [31,32,38].

PON1 has atheroprotective and anti-inflammatory properties [39]. PON1 inhibits the formation of oxidized LDL through hydrolysis of the lactone ring in homocysteine thiolactone (HTL) molecule It can also degrade some oxidized lipids [39]. Indeed, PON1 modulates the metabolism of RNS, stimulates nitric oxide production, and reduces macrophage foam cell formation [39]. 

The PON1 arylesterase and lactonase activities contribute to the maintenance of the physiological functions of HDL in both cells and tissues. Changes in PON1 activities and HDL function have been associated with physiological conditions such as pregnancy and aging, as well as pathophysiological conditions such as atherosclerosis, diabetes, cerebrovascular and neurodegenerative diseases, iron overload, renal disease, drug metabolism and detoxification of organophosphate compounds [25,40–43]. 

A diet rich in fruits and vegetables, olive oils, polyphenols, and flavonoids such as quercetin, increases the activity of the enzyme PON1, contributing to the reduction of oxidative stress in the degeneration process [44–49].

2.3. Paraoxonase 3

PON3 is an antioxidant hydrolase enzyme with approximately 40-kDa, synthesized in the liver. In plasma, PON3 is bound to HDL and apolipoprotein-AI and possesses strong anti-oxidant properties but its concentration is about two orders of magnitude less abundant than PON1 [63]. 

PON3 is also expressed at low levels in the kidney [32]. PON3 was the last enzyme in the paraoxonase family genetic cluster to be described. Currently, very little is known about its function and physiological characteristics in humans. The enzymes PON3 and PON1 show some similarities in structure and hydrolase activity. Regarding the structure, both enzymes have three highly conserved cysteine (Cys) residues in positions −41; −283, and −351 in the protein chain [64]. As for enzyme activity, PON3 can hydrolyze cyclic carbonate esters and lactones rapidly, mainly drugs such as statin lactones. 

The arylesterase activity of PON3 is almost undetectable when compared to PON1 [65]. PON3 participates in tissue homeostasis against oxidative stress in the same way as paraoxonases-1 and -2. Indeed, in vitro, PON3 hydrolyzes some products derived from the oxidation process, such as both oxidized phospholipids and lipid (hydro)peroxides in oxLDL, suppressing the oxidation propagation cascade in other lipids and phospholipids [66]. 

Indeed, previous studies have indicated that the decrease in the concentration of PON3 is associated with coronary artery disease, obesity, and chronic liver disease [67–69]. In addition, in HDL particles from patients with systemic lupus erythematosus and type one diabetes, it was observed that the PON3 content was depleted, being associated with subclinical atherosclerosis [70]. 

Moreover, recent studies have described increased expression of PON3 in different types of tumor cells [56,71]. Currently, there are six SNPs described in the promoter region of the PON3 gene: C-567T, A-665G, C-746T, G-4105A, T-4970G, and A-4984G. These polymorphisms have little or no influence on the PON3 concentration [66].

3. Neurodegenerative Diseases

The healthy human brain has about 100 billion neurons, which are interconnected by biochemical mechanisms called synapses. In this way, through the neuronal circuits of the brain, the cellular base of memories, thoughts, sensations, emotions, movements, and skills is created. When irreversible changes occur in the brain niche, the neurodegeneration process begins, leading to the different types of neurodegenerative diseases, Figure 4. 

This process may be associated with changes in neurons, and glial cells, as well as from metabolic changes, or systemic diseases that alter the permeability of the blood-brain barrier (BBB) and can alter cognitive functions [72,73]. Thus, the brain environment becomes susceptible to pathological changes, with loss of cell function, cell death, increased neuroinflammation, oxidative stress, and lipid peroxidation. Together, these factors affect both the biochemical and physiological properties of the myelin sheath [74]. The formation of myelin in the CNS is derived from the involvement of the macroglia plasma membrane around the axon. 

The brain structural composition consists of proteins (about 15–30%) and lipids (70–85%): Cholesterol (mostly non-esterified), phospholipids, and glycolipids in a 2:2:1 ratio. In addition, the brain has about 20–30% of the body's total cholesterol [74,75]. Cholesterol exchanges between the central nervous system and blood circulation are highly limited; this helps to avoid tissue damage and injury [75–77]. The association between cholesterol and neurodegenerative diseases is longstanding [78]. Changes in lipid metabolism in the brain are associated with protein aggregation and the onset of senile plaque formation [79]. 

In addition, in several recent studies, cholesterol content and changes in the Apo-E gene have been associated with risk factors for worsening cognitive function and the development of dementia [80,81]. Moreover, the Apo-Eε4 genotype has been associated with β-amyloid and tau protein aggregation, both associated with the development of dementia [82–85].

Interestingly, Thorvaldsson et al. [86] observed a non-linear association between total cholesterol concentration (low and high values) and worsening cognition. In addition, total cholesterol levels decrease over time and are associated with the rate of cognitive decline. On the other hand, Bennett et al. [87] did not find an association between plasma total cholesterol and fractions, and plasma triglycerides with amyloid load in old age. However, it is possible that changes in lipid metabolism could occur in the CNS with no detected modifications in blood circulation.

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