In humans, the Paraoxonase (PON) family of enzymes (PON-1, PON-2, and PON-3) are encoded by three adjacent genes located on human chromosome 7q21.3. These three enzymes share similar activities and have a 90% structural similarity. The PONs are calcium-dependent esterases with an approximate molecular mass of 40–45 kDa; additional structural properties are reviewed in [1]. PON-1 and PON-3 are mainly synthesized in the liver and circulate bound to high-density lipoprotein (HDL) in serum, whereas PON-2 is synthesized locally in tissues such as the brain, kidney, liver, and testis ^[2][3][4][2,3,4]. ThWe researhers aand others have demonstrated well-established roles for diminished expression and activity of PONs in cardiovascular and renal disease both clinically and experimentally, and this has been previously reviewed [1]. Clinically, PON-1 has well-known cardioprotective roles in patients with stable coronary artery disease [5], systolic heart failure [6], stable chronic heart failure [7], and chronic kidney disease ^[6][8][6,8]. Experimentally, PON-1 not only has cardioprotective roles in chronic kidney disease [9], but also renal anti-inflammatory and anti-fibrotic roles in the setting of chronic hypertension [10] and renal ischemia [11]. Additionally, PON-2 has demonstrated a cardioprotective role, which may be associated with its ability to improve mitochondrial function and diminish reactive oxygen species generation [12]. Furthermore, PON-3 has recently been shown to participate in the metabolism of cardiotonic steroids in settings such as hypertension and chronic kidney disease [13]. In the current entwory, the researchers rek, we review the important roles PONs play outside of these established cardiovascular functions by examining a variety of roles for PONs in common neurodegenerative diseases as well as other associated neurological disorders.

Neurodegenerative diseases (ND) are a broad range of disorders characterized by neuronal tissue damage and loss of function, leading to cell death ^[14][20]. The etiology of ND is multifactorial and still not fully understood ^[15][21]. However, many of these disorders seem to have common cellular and molecular mechanisms underlying the pathogenesis; for example, certain toxin exposures, increased oxidative stress, and decreased antioxidant activity ^[16][22]. PON enzymes serve as an important physiological redox system which participates in protecting against cellular injury caused by genotoxic and oxidative damage. PON-1 is a hydrolytic lactonase enzyme that is synthesized in the liver and circulates bound to HDL. It provides the antioxidant property that prevents LDL and HDL oxidation and contributes to much of the anti-oxidative and anti-atherogenic activities that have been attributed to HDL ^[17][18][23,24]. It also protects HDL and LDL from oxidative stress through the elimination of ROS produced by metabolism. PON possesses peroxidase-like activity that can contribute significantly to the protective effect of PON against lipoprotein oxidation ^[19][25]. PON enzyme activity in serum has been correlated with protection against oxidative damage ^[20][21][26,27]. Oxidative stress plays an essential role in the pathogenesis of many ND, even though the exact mechanistic links are not fully elucidated. Nevertheless, many studies have highlighted the links between PON-1 and ND progression ^[22][23][24][28,29,30].

PON-1 protects against atherogenesis by metabolizing oxidized lipids. Its essential role as a protective factor against atherogenesis continues to attract more attention in epidemiological studies ^[25][26][31,32]. Studies have demonstrated PON-1’s role in ischemic stroke, one of the top neurological disorders linked with atherosclerosis ^{[27][28][29][30][31]}[33,34,35,36,37]. Beyond stroke, pesticide exposure has consistently been associated with the development of ND ^[32][33][38,39]. Exposure to pesticides results in induced oxidative stress, mitochondrial dysfunction, and impairment of the ubiquitin–proteasome system, mechanisms that are related to neuronal cell death in ND ^[34][40]. PON-1 detoxifies xenobiotics, including pesticides, and also hydrolyses bioactive toxic oxon metabolites, such as parathion, diazinon, and chlorpyrifos, converting them into nontoxic metabolites ^[35][36][41,42]. In humans, serum PON-1 levels and activity show up to a 40-fold interindividual variation and can be genetically influenced by common polymorphisms of the PON-1 gene ^[37][43]. Several polymorphisms have been identified in the promoter and coding regions for the PON-1 gene. The coding region polymorphisms include a methionine/leucine substitution at position 55 (Leu-Met-55) and an arginine/glutamine substitution at position 192 (Gln-Arg 192) ^[38][44]. Both have been shown to influence serum levels and biological activity. Studies report the PON-1 L55M polymorphism as a risk factor in AD while the Q192R polymorphism demonstrated a protective function ^[39][45]. On the other hand, studies have also found that the presence of the PON-1 R192 allele raises the risk of cardiovascular disease ^[40][46]. Further, it was observed that the PON-1 L55M polymorphism causes a decrease in PON-1 levels while the PON-1 Q192R mutation causes an elevation in enzyme levels. Therefore, PON-1 may serve as a potential biomarker for determining the severity and prognosis of ND in subjects with different genotypes. Additional clinical studies indicate that low PON-1 activity could be a potential risk factor for ND. Because PON-1’s esterase, lactonase, and arylesterase activities are significantly affected by its polymorphisms, considerable attention has been devoted to understanding the role of PON-1 in the emerging risk of ND. Here, thwe researchers eexamine the molecular mechanisms of PON-1 status as it relates to these disorders.

3. Overview of PON-2 and Its Neurological Associations

Paraoxonase 2 (PON-2) is the oldest member of the PON family. Compared to the other two PON genes, PON-2 is found in many tissues throughout the body, with high expression in the brain, heart, and lungs ^[41][84]. PON-2 uses calcium to hydrolyze lactones, esters, and aryl esters and functions as an antioxidant, reducing the levels of ROS. In addition, PON-2 is found in the endoplasmic reticulum (ER) and mitochondria, binding to coenzyme Q10 and preventing superoxide formation ^[42][85]. PON-2 plays an important role in the brain and has critical neuroprotective properties. Its expression has been found to be the highest in dopaminergic regions, specifically the nucleus accumbens, striatum, and substantia nigra. Astrocytes, in comparison to neurons, have significantly higher levels of PON-2, and a deficit of expression in both cell types can lead to high levels of oxidative stress and the inability to recover from toxicity, which can subsequently lead to death ^[43][15]. Sex and age can be major determinants of PON-2 expression. Since PON-2 has a critical role in the regulation of oxidative stress and is an anti-inflammatory factor, it is important to consider sex and age as variables when assessing PON-2 expression ^[43][44][15,86]. The association between polymorphisms of PON-2 and enzymatic activities in the neurodegeneration process still needs to be understood. Some studies show that low levels of PON-2 expression, due to its potent neuroprotective characteristics, impact various neurodegenerative diseases and conditions, such as AD, PD, ALS, and cerebral ischemia-reperfusion injuries ^{[45][46][47][48]}[69,87,88,89]. Moreover, PON-2 may be a potential therapeutic target in brain tumors, as it can aid in modulating the levels of oxidative stress, apoptosis, and cellular proliferation in tumors ^[49][90].

4. Overview of PON-3 and Its Neurological Associations

Paraoxonase 3 (PON-3) is the last member of the PON family of hydrolytic enzymes and is also perhaps the least studied of the three. PON-3, a calcium-dependent glycoprotein, is characterized by its anti-inflammatory, antioxidant, and anti-apoptotic properties [1]. Primarily synthesized in the liver and kidney, PON-3 is found tightly bound to HDL as it circulates the blood, in mitochondria of specific tissues, and in the endoplasmic reticulum of intestinal cells ^[50][99]. This enzyme takes on the role of hydrolyzing lactones, or cyclic esters, and eicosanoids, or signaling molecules derived from polyunsaturated fatty acids ^[1][50][1,99]. These characteristics are shared with PON-1, the more widely studied PON, though there are notable differences between the two family members. For example, PON-3 does not possess organophosphatase activities and its circulation is found in lower concentrations compared to PON-1 ^[1][50][51][1,98,99]. In this rentry, the researchersview we summarize some of the key studies establishing the links between PON-3 and neurological disorders, but more research is clearly needed to gain insight into these associations. Current research suggests that PON-3 plays a role in neurodegenerative diseases that are associated with brain inflammation and oxidative lipid injury ^[52][17]. In particular, this list of diseases includes AD and ALS ^[50][51][52][17,98,99]. Other studies have also indicated that PON-3 dysfunction contributes to neurotoxicity and cerebral infarction ^[53][54][100,101]. Since PON-3 shares similar synthesis, expression patterns, HDL-binding in blood, and protective activities with PON-1, it is believed to exert similar effects ^{[1][51][52][54]}[1,17,98,101]. Like PON-1, PON-3 dysfunction is recognized for its adverse effects in renal and cardiovascular processes [1]. After observing that PON-3 protein circulates to other regions such as the brain, researchers have studied the association between neurological diseases and PON-3 expression. Overall, a theme emerges that the neuro-associated diseases examined have some correlation with reduced PON-3 gene levels or mutated PON-3 protein. Thus, current studies of PON-3 in neurodegeneration and neurotoxicity have implications for the enzyme’s preventative and protective effects on the brain ^{[50][51][52][53][54]}[17,98,99,100,101]. This evidence likewise suggests that, following synthesis in the liver and kidneys, PON-3 products circulate to other systems in the body and play protective roles. Ultimately, PON-3 warrants further research and thorough analysis in order to understand its localization, physiologic significance, prospects in treatment, and diagnostic potential ^[1][55][1,102].