Paraoxonase Role in Human Neurodegenerative Diseases Part 3

The cluster of PON genes is highly polymorphic, being able to present wide variability and different frequencies between ethnicities, as well as in different diseases. The Q192R polymorphism was a discriminating factor between AD and VD; however, there was no difference in genotypic distributions between groups [199]. 

The relationship between the PON gene cluster and memory has been the focus of scientific research. Research shows that there is an inextricable link between the PON gene cluster and memory. The PON gene cluster is a group of genes with similar biochemical functions that can affect the physiological and biochemical processes of the human body, including metabolism, antioxidants, immunity, and neuroprotection.

A recent study showed that one member of the PON gene cluster, the PON1 gene, is closely linked to memory. This study proves that PON1 protein defects caused by PON1 gene mutations will significantly reduce the brain's utilization of oxygen, thereby leading to a decline in cognitive function. Other studies have also found that the PON2 gene is related to brain cognitive ability and intelligence level.

The findings from these studies provide us with a deeper understanding that we should not only focus on the health of our bodies but also the health of our brains. Maintaining healthy PON gene cluster function is one of the important factors in maintaining the health of our bodies and brains. By maintaining a healthy lifestyle, such as eating well, exercising regularly, getting enough sleep, and reducing stress, we can help our PON gene cluster maintain normal function, thereby improving memory and cognitive function. In addition, we can exercise our brains and enhance memory and cognitive abilities through activities such as cognitive training, learning new skills, and reading.

Taken together, the link between the PON gene cluster and memory reveals the close relationship between body and brain health. By maintaining a healthy lifestyle and actively exercising our brains, we can improve our memory and cognitive abilities, leading to a healthier and more fulfilling life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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On the other hand, the association between Q192R, Alzheimer's disease, and coronary artery disease (CAD) is controversial. Scacchi et al. [200] have observed a low frequency of the R allele in individuals with AD; the adjustment for age, gender, and polymorphism of Apo-Eε4 highlighted that the genotype PON1 RR was a protective factor for AD, whereas, for young individuals with CAD, this genotype was associated with a risk factor [200]. 

Similar results for the R allele have been reported in the Chinese population. The presence of the R allele indicated a protective factor against the development of AD [201]. However, in older Singaporean Chinese patients, the R allele was associated with a worse functional state, the presence of neuropsychiatric symptoms, and severe advanced dementia in patients with mixed dementia [202]. 

Controversially, in a French population, the R allele seemed to be a risk for dementia, together with the T allele (C-107T), independently of the Apo-Eε4 allele [203]. However, SNP Q192R of the PON1 gene has not been associated with the risk of AD in Italian and Polish populations [204,205]. PON1 is an exogenous acetylcholinesterase inhibitor (ChEI) [206]. 

The influence of SNP Q192R in response to treatment with ChEIs has been evaluated in a small cohort of patients with AD [207]. Individuals with AD and the R allele had a better response to therapy compared to homozygous QQ individuals [207]. The authors pointed out that the allele was associated with a greater capacity for hydrolysis of the enzyme; for this reason, there may be a synergism in the metabolism of drugs such as donepezil, galantamine, and rivastigmine, which may improve their effectiveness [207]. 

On the other hand, another study with three PON1 SNPs (Q192R, L55M, and A−162G) showed no change in response to treatment with acetylcholinesterase inhibitors in patients with AD [208]. Several factors can change the therapeutic response to acetylcholinesterase inhibitors. However, association studies of PON1 enzymatic activity and polymorphisms with environmental exposure, eating habits, genetic factors of susceptibility to AD, and drug metabolism-associated polymorphism, are lacking [209–211]. 

In patients with Alzheimer's disease, the homozygous TT genotype (PON1 C-107T) was associated with a change in the distribution of lipoprotein cholesterol with a higher prevalence of a smaller and denser LDL [212]. It has also been associated with an increase in plasma oxidized LDL levels [212]. Oxidative stress in Alzheimer's disease contributes to lipoprotein oxidation, increased neuroinflammation, neuronal loss, and endothelial damage [213,214]. 

However, these are multifactorial mechanisms that cannot be attributed to the presence of a single polymorphism. In addition, in an Italian case-control study, no association was observed between the T allele (C-107T) and the development of AD. Indeed, no Apo-Eε4 genotype association was found [215]. Another polymorphism in promoter region gene PON-1, the SNP C-108T, has been associated with the development of AD. 

The T allele was more frequent in patients with AD, and the homozygous genotype (TT) was associated with low arylesterase activity of PON1 [216,217]. However, the relationship between AD and the SNP PON1 C-107T and C-108T still needs to be clarified. Erlich et al. [58] genotyped 29 SNPs in the PON gene region in a large cohort composed of Afro-descendants and Caucasians with AD. 

It was observed that the location of positive associations for the development of AD was found in distinct regions in the PON gene in both ethnicities. Sliding window haplotype analyses showed that SNP C-161T was associated with AD; however, SNP C-161T was not associated with AD in the French AD population [218]. 

In addition, the authors established an association pattern in which the presence of the T allele had a deleterious effect, independently or in association with other genotypes [58]. Moreover, in this study, it was shown that these SNPs, A-107G, Q192R, L55M in PON1 and C311S in PON2, before associated with AD risk may not act independently, but rather in linkage disequilibrium with other polymorphisms that are associated with the pathophysiology of AD. 

These results can partially explain the inconsistencies among the studies that investigate PON1 Q192R and L55M polymorphisms as associated with the development of Alzheimer's disease. In the brain tissue of AD patients, a high frequency of the homozygous genotype MM PON1 L55M was observed [219]. In addition, patients with homozygous MM had a 2.5-fold increase in the proportion of Aβ42/Aβ40 in the frontal cortex compared to control and individuals with AD carrying LL genotype [219]. Moreover, AD patients with R allele (Q192R) had a significantly lower Aβ42 / Aβ 40 ratio compared to Q192Q homozygous AD patients [219]. 

In addition, individuals with M allele (L55M PON1) showed a decrease in the total amount of nicotinic receptor and choline acetyltransferase (CHAT) activity in the temporal cortex [219]. A large cohort of clinical cases confirmed this study by AD autopsy (n = 1.066) [220]. The M allele of the L55M SNP was associated with a risk of developing AD in men. Men and women with the MM-QQ genotype have a higher survival rate (about 2.5 years) and later age of disease onset (about 1.5 years). 

In addition, AD individuals with R allele had a decrease in both, Aβ42 levels and Aβ42/Aβ40 ratios. In the hippocampus and frontal cortex, patients with the MM genotype showed a decrease in their Aβ40 concentration and an increase in Aβ42/Aβ40 ratios compared to both, LM and LL genotypes. In men with the MM genotype, it has been observed more neuritic senile plaques than those with the LL genotype in the fusiform gyrus and frontal cortex [220]. 

On the other hand, in the meta-analysis, individuals with the PON1 polymorphisms Q192R and L55M were not susceptible to AD [221]. PON1 activity is low in different forms of dementia [40,199,222–226]. The reduced activity of PON1 was associated with an increase in the atherosclerotic process in patients with AD [227]. A decrease in paraoxonase activity in patients with AD was associated with Apo-Eε4 isoforms and both total cholesterol and elevated LDL-cholesterol [228]. 

Indeed, the ratio between PON1 and platelet-activating factor acetylhydrolase (PAF-AH) activity was correlated to the increase in oxidized LDL [229]. Moreover, 8-hydroxy-2'- deoxyguanosine (8-OHdG), an oxidized product derived from deoxyguanosine, formed after the oxidation process in DNA, has been negatively correlated with PON1 activity in AD patients [230]. 

However, the proportion between arylesterase PON1 activity and ApoAI showed an inverse relationship with the concentration of both total and phosphorylated tau proteins in patients with AD in cerebrospinal fluid [231].

3.4. Parkinson's Disease

Parkinson's disease (PD) is featured by a strong decrease in the production of dopamine in the substantia nigra, due to the degeneration of dopaminergic neurons. This process is slow; initially, there is an impairment of the motor system, and in more advanced cases non-motor symptoms are observed. Currently, about 1% of people in the world aged over 60 years develop PD. 

Clinically, patients show changes in the motor system, such as bradykinesia, rest tremor, and stiffness, symptoms known as parkinsonism [232]. However, critically ill patients have non-motor changes, including anosmia, constipation, pain, anxiety, depression, and psychosis. Initially, cognitive disorders are mild, evolve to moderate, and then progress to dementia [233]. 

The pathophysiological characteristics of PD include a slow and progressive degeneration of dopaminergic neurons, depletion of striatal dopamine, disappearance of neuromelanin, and the appearance of intracellular Lewy bodies, derived from the incorrect folding of α-synuclein protein [234,235]. During the progression of PD, there is an increase in lipid (hydro) peroxidation and altered mitochondrial function, due to electron leakage, and consequent formation of the hydroxyl radical and hydrogen peroxide, associated with the exhaustion of the redox system. 

These factors together contribute to increased dopamine oxidation in the synaptic cleft and neuronal death leads to the development of dementia [236–238]. The association between Parkinson's disease and the PON1 enzyme is because toxic metabolites such as dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), have been associated with the development of PD. 

MPTP has a chemical structure similar to some organophosphates [239,240]. Moreover, organophosphates are bioactivated in cholinesterase inhibitors after metabolization by cytochrome P 450 systems, and the oxon (toxic) form is hydrolyzed by PON1. In addition, the B allele of the SNP Q192R PON1 has been associated with the development of PD in the Japanese population [241]. 

However, the association between SNP Q192R was not associated with the development of PD in other populations, such as the Caucasian and Chinese populations [242–244]. SNP L55M was considered an independent risk factor for the development of PD in different populations. The frequency of the M allele was higher in Parkinson's patients, and the estimated relative risk was approximately two times higher when compared with homozygous individuals for the L allele [245,246]. 

Additionally, environmental exposure to diazinon, chlorpyrifos, and parathion in individuals with homozygous genotypes QQ and MM (SNPs Q192 and L55M, respectively), have been associated with Parkinson's development by up to three times [247]. 

Indeed, the frequent use of organophosphate chemicals was associated with PD at a chance of up to 71%. Individuals with both homozygous genotypes MM and QQ had an approximately six-fold chance of developing PD [248]. The presence of these polymorphisms characterizes a "slow metabolization" of organophosphates. However, in other studies, the association between PON1 and PD polymorphism has not been observed [205,249–251]. 

Polymorphism in the PON1 G-832A promoter region was associated with PD. The A allele was more common among controls than in PD patients and may have a protective effect [252]. In addition, SNP G-832A was in an imbalance with PON1 C-909G polymorphism. [252]. The polymorphism present in the PON1-promoting region, C-909G, has been associated with increased expression of the PON1 gene [253]. 

In patients with PD living in a rural area exposed to pesticides, the serum activities of acetylcholinesterase (AChE) and PON1 were reduced. A linkage disequilibrium was observed between the PON1 and the AChE locus. The polymorphism of the PON1 C108T promoter region and the AChE deletion (∆AChwasere associated with Parkinson's development approximately two times [254]. The authors suggested that hereditary interaction at the AChE and PON1 locus may increase the occurrence of insecticide-induced Parkinson's disease [254]. Serum reduction in total cholesterol, LDL, PON1, and urate were associated with PD progression. 

In addition, serum ferritin concentration was inversely correlated with PON1 activity [255]. The association between ferritin and PON1 may be a link between inflammation and the enzymatic antioxidant system [43]. Decreased serum paraoxonase activity in PD patients has been associated with increased oxidative stress, lipid peroxidation, and changes in iron metabolism markers [256–258].

4. Conclusions

PON1 activity and polymorphisms have been associated with neurodegenerative diseases. However, taking into consideration that PON1 may have plasma activities that do not reflect the enzyme activity in the central nervous system, relatively little is known to date about the real role of PONs in the central nervous system or their mechanism of action. 

Data have suggested that the Q192R and L55M intronic polymorphisms are risk factors for the development of neurodegenerative diseases. However, several other studies describe contradictory results. Although the role of PONs is described as hydrolase enzymes in several diseases, robust studies are still lacking to clarify the association between polymorphisms of the PONs gene cluster, including PON2 and PON3, and enzymatic activities in the neurodegeneration process. 

Studies at the cellular level are necessary to understand the physiological functions of PONs in macro and microglia cells and neurons. Differences in the distribution and specificities of PONs in the human body indicate that there may be specific tissue activity for each enzyme. 

Nevertheless, taking all studies together, paraoxonase seems to have a role in the decrease and/or prevention of the neurodegeneration process associated with the imbalance of the redox system. Further studies in this direction could provide enough information that would lead to new clinical-pharmacological interventions.

Author Contributions: Writing-original draft preparation, C.O.R., D.L., and S.P.B.; writing-review and editing, C.O.R., D.L. and S.P.B.; funding acquisition, S.P.B. All authors have read and agreed to the published version of the manuscript.

Funding: This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Instituto Nacional de Ciência e Tecnologia–Fluidos Complexos (INCT-FCx); Instituto Nacional de Ciência e Tecnologia em Medicina Regenerative (INCT-Regenera), all from Brazil.

Acknowledgments: The figures in this publication were created in BioRender.com

Conflicts of Interest: The authors declare no conflict of interest.

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