Overview on Parkinson’s disease: pathophysiology, and experimental models

Parkinson's disease, a neurodegenerative disease, is caused by dopaminergic neurons death and accompanied by rigidity, and postural instability, as well as bradykinesia. The cause of these neurons’ death is still unclear. Since the dopaminergic neurons couldn’t regenerate, therefore Parkinson's disease couldn’t be cured. Thus, over the past decades, significant effort has been made to explore the etiology of Parkinson's disease development and ascertainment. This review aimed to highlight the progress that has been made in understanding Parkinson’s disease pathophysiology. The role of oxidative stress, neuroinflammation, and apoptosis in the development of PD has been discussed. It has been noticed that oxidative stress, inflammation, and apoptosis are working together to develop Parkinson's disease, and each of these factors affects each other. Additionally, the experimental models and their drawbacks have been emphasized. Additionally, the mechanism of inducing Parkinson’s disease (i.e., inducing neuroinflammation and oxidative stress) by neurotoxin has been highlighted.


Introduction
Parkinson's disease (PD) is second to Alzheimer's disease as the most prevalent neurodegenerative disorder throughout the world [1]. Paralysis agitans was first medically described as a neurological syndrome by J. Parkinson in the 19 th century in the book ''Essay on the Shaking Palsy'' and renamed PD by Jean-Martin Charcot [2, 3].
Clinically, PD is characterized by motor dysfunction, i.e., rest tremors, bradykinesia, postural instability, and rigidity. Also, psychiatric symptoms are involved, including depression and anxiety, as well as autonomic dysfunction manifestoes, i.e., constipation and hypotension. Besides, it is characterized by paresthesia, olfactory dysfunction, and sleep disorders [4]. A review of incidence studies reported that the PD incidence rises with age to a peak occurring in the seventh decade of life and it continues to rise after this age in some studies [5].
Pathologically, PD is associated with Lewy bodies (LBs), dopaminergic neuronal cytoplasmic inclusions. These are the hallmarks of PD, as they are not detectable in healthy individuals. In 1997, LBs were reported to contain aggregates of α-synuclein (α-Syn) [6].
In this review, the pathogenesis of PD, and neurotoxin models will be discussed.

The pathophysiology of PD
Pathologically, PD is characterized by hallmarked dopaminergic neurons lost in the substantia nigra and the appearance of LBs that are primarily comprised of fibrillar α-Syn [7].
Genetically, studies on familial PD have identified mutations in single genes in monogenic PD. In particular, mutations, which give rise to PD, are located in the α-Syn-encoded genes, dardarin, vacuolar protein sorting-associated protein 35, parkin ligase, deglycase DJ1, and acid β-glucosidase [8].
Despite mutations in these genes being infrequent and only exist in less than a tenth of all PD cases [9], they have discovered key processes and molecular players in the etiology of PD. This can be clarified by the gene (SNCA), which is linked to PD at a neuropathological and genetic level. Additionally, LBs and α-Syn are recognized in familial-and idiopathic-PD. Besides the mutations in SNCA and copy number variations present in monogenic PD [10], common SNCA mutations are linked to an increased risk of idiopathic PD [11].
Because there is no monogenic inheritance pattern in most PD patients (90%), the disease is considered idiopathic. Sporadic PD has a multiple-factorial etiology; environmental and genetic factors work together to determine an individual's liability to disease [12, 13].

The role of oxidative stress in PD
Mounting evidence has pointed that oxidative damage and mitochondrial dysfunction result in a cascade of events and eventually contribute to dopaminergic neurons degeneration [14]. This notion was supported by the assessment of the postmortem brain sections, in which elevated levels of 4-hydroxy-2-nominal, a lipid peroxidation by-product Postmortem tissues from the brain of PD patients have shown depletion in the amount of glutathione (GSH) in substantia nigra compacta compared to the controls [20]. Glutathione is generated in the cytoplasm but it is transported to the mitochondria to work as an anti-oxidant [21]. Since apoptosis is induced by oxidative stress, the mitochondrial GSH is considered a crucial marker of oxidative stress assessment. Also, mounting observations indicated that complex-I dysfunction causes higher production of ROS and subsequently a reduction in GSH. This reduction can result from a decreased synthesis of GSH by the suppressing of glutathione reductase, or rising glutathione disulfide level [22, 23]. Oppositely, reduced GSH level leads to complex-I activity impairment, and overall mitochondrial function Iron is pivotal for most human cells. Indeed, it is a cofactor for important proteins to maintain the normal neurons function, like tyrosine hydroxylase, an important enzyme for the synthesis of neurotransmitters [25]. Iron can contribute to ROS generation by the reaction of ferric/ferrous with superoxide anion radical, and hydrogen peroxide, producing the hydroxyl radicals, which trigger neurotoxicity with DA oxidation [26].

The role of inflammation in PD pathogenesis
The inflammatory process, which is a protective mechanism against any infection, damage, or injury, is mediated by several immune cells, i.e., microglia, neutrophils, and macrophages The implication of neuroinflammation in PD pathology is based on quite a lot of research of evidence suggesting that neuro-inflammatory processes could possess a causal role in PD development [31]. Also, inflammation is suspected to be a melting point for genetic and also environmental factors that provoke PD pathogenesis [7].
Microglia constitute about a tenth of all glia and are usually resting in the adult brain playing beneficial housekeeping roles, as removal of toxic substances, synaptic remodeling, neuronal repair, and synaptic pruning [32]. Environmental challenges, morphological changes, intracellular molecules, and surface antigens could provoke microglial activation [33]. α-Syn and soluble molecules liberated from dying neurons could also activate the microglia [33]. In the activation state, the microglia up-regulate many receptors implicated in inflammation, and could also generate potential neurotoxins, i.e., superoxide anions

The role of apoptosis in PD pathogenesis
Apoptosis starts with specific internal/external signals and plays a substantial role in aging, neoplasm, and neurological disorders

Neurotoxin-based model of PD
Epidemiological studies have affirmed that prolonged exposure to rural chemicals, i.e., paraquat and rotenone elevate the risk of PD development [63]. Dopamine structural analogs, like MPTP, and 6-hydroxydopamine (6-OHDA), have been reported to selectively damage dopaminergic neurons and induce parkinsonism.

3.1.
The 6-hydroxydopamine model of PD 6-Hydroxydopamine is the first neurotoxin used to induce PD because it could induce mitochondrial dysfunction of dopaminergic neurons [64]. Since 6-OHDA cannot cross BBB, it has to be injected intra-cerebrally. 6-Hydroxydopamine is transferred into the neurons by the DA transporter and then suppresses the activity of mitochondrial respiratory chain complex-I [65, 66]. In mitochondrial, 6-OHDA can also suppress the complex-IV activity and reduce membrane potential [67].
Once inside the neurons, 6-OHDA produces H 2 O 2 , and superoxide from its metabolic degradation or oxidation. ROS cause protein-and DNA oxidation, and lipid peroxidation, and eventually lead to oxidative stress and mitochondrial impairment [68, 69]. 6-Hydroxydopamine could increase glutamate, and lower the striatal glutamine, resulting in an imbalance between excitatory and inhibitory brain processes, causing long-term irregularities in activities of the glutamate system and After crossing the BBB, MPTP is converted by MAO-B into 1-methyl-4-phenylpyridinium ion (MPP + ), its active form, and then carried by the DA transporter inside the dopaminergic neurons, where it suppresses the mitochondrial complex-I activity [76]. It has been re-assessed following MPTP treatment through the intranasal route, resulting in depletion of striatal DA, accompanied by PD symptoms [77].

The paraquat model of PD
Paraquat is an herbicide that has been got great interest due to its chemical structural similarity to MPP + [81]. Paraquat has been used to induce the PD model as it can penetrate the BBB by the neutral amino acid transporter since the L-valine treatment significantly reduced the paraquat penetration of BBB [82]. Paraquat impairs the redox recycling of GSH and thioredoxin inducing oxidative stress [83].
However, paraquat administration causes acute toxicity in many organs, particularly lung tissues; thus, it may affect motor performance and cause a high mortality rate [84]. Additionally, the use of the paraquat model in examining neuroprotective therapies is limited due to the lack of paraquat-induced striatal DA depletion [85].

The rotenone model of PD
Rotenone is an isoflavone found in the roots and stems of the Lonchocarpus and Derris, and due to its high lipophilicity, it can cross BBB [86]. As soon as ROT is in the dopaminergic neurons, it inhibits the complex-I activity, resulting in an elevation in ROS production and mitochondrial dysfunction [87] Lipid and also glutamine metabolism alterations by rotenone play a pivotal compensatory role in PD modeling [88]. ROT has become of high interest following the seminal paper by the Greenamyre group in 2000, it was continuously IV infused into the back of Lewis rats at a concentration of 3 mg/kg/day [89].

Conclusion
Significant advances in understanding the pathogenesis of PD have been concluded from the epidemiological findings, experimental methods, and pathological manifestations. Signaling pathways have been detected, accompanied by mitochondrial homeostasis impairments, and protein accumulation, and are likely to be involved in PD etiology. Additionally, a substantial advance has been made in PD modeling. However, each model has advantages and limitations. Further research is needed to develop the currently used models or new models to recapitulate the human PD.

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All authors have read and agreed to the published version of the manuscript.

Availability of data and materials
Data analyzed during this study are all included in the main manuscript.

Competing interests
No competing interests were declared by the authors.

Funding statement
No funding source was received