Pathological hallmarks of Parkinson disease (PD) include accumulations of a-synuclein aggregates known as Lewy bodies or neurites in certain areas of the central nervous system, such as the basal ganglia, dorsal motor nucleus of vagus (DMV), olfactory bulb (OB), locus coeruleus (LC), intermediolateral nucleus in spinal cord (IML), celiac ganglia, and enteric nervous system (ENS) ^[1].

New research indicates that Parkinson’s disease (PD) neuropathology could be caused by environmental stressors and the natural process of aging itself. Exposure to environmental toxins, drugs of abuse, or the stress of aging may lead to chronic low-level inflammation in the brain, leading to something known as “inflammageing,” and thus to neuron cellular senescence. Pathologically, Parkinson’s patients typically display damage in the substantia nigra pars compacta and pontine locus coeruleus regions of their brains characterized by depigmentation, neuronal loss, and gliosis. By the time symptoms manifest themselves, approximately 60–70% of neurons from this region have already been lost ^[2]. Genetic factors have been estimated to account for roughly 25% of the risk associated with Parkinson’s disease, and genetic variants associated with it vary both in terms of frequency and risk. While rare mutations within individual genes (known as monogenic causes) may contribute to its development (known as monogenic causes), these were generally discovered through linkage analysis in affected families using linkage analysis; some common genetic variants that only contribute a small amount to risk were also discovered via genome-wide association studies (GWASs), including many common genetic variants that contribute an intermediate risk, such as GBA or LRRK2 variants. Genetic classification of Parkinson’s can lead to various treatment approaches and prognoses for each subgroup, often depending on age of onset, family history, and pathogenic variant presence; age at onset, family history and presence of pathogenic variants are frequently used as criteria for stratifying this form of PD. Monogenic forms may or may not represent typical forms of idiopathic PD. Importantly, some genes involved in monogenic PD have also been identified through GWAS studies as common variants. One such gene, SNCA, which was discovered through these analyses to have common variants, is also implicated in monogenic PD pathogenesis, supporting the role of a-synuclein. Other pathways may also play a part in its pathogenesis, such as tau aggregation, which is linked with other neurodegenerative conditions such as Alzheimer’s and frontotemporal dementia ^[3]. Familial Parkinson’s, also referred to as Mendelian or monogenic PD, is characterized by rare yet high-penetrance genetic variants that increase risk. Autosomal dominant (e.g., SNCAA53T and VPS35D620N) and recessive forms of familial Parkinson disease have been identified using linkage analysis in families with the help of next-generation sequencing technologies, though only 5–10% of cases fall under these single gene variants. Conversely, low-penetrance genetic variants with more frequent associations with sporadic Parkinson’s disease have been identified through genome-wide association studies (GWASs). At first glance, distinguishing familial from sporadic disease may help with diagnosis, prognosis, and genetic counseling for at-risk family members; however, such classification may obscure shared genetic or biological mechanisms that underlie them both. An example is that both rare and common genetic variants associated with SNCA have been shown to increase Parkinson’s risk, underscoring its role as an aSyn-mediated disease mechanism. Missense variants in SNCA such as p.A53T, p.A30P and p.E46K cause autosomal dominant familial Parkinson disease, while the common risk variant SNCArs356168 occurs in approximately 40% of European-ancestry populations and has only modest effects on disease risk ^[4]. SNCA, or synuclein complex A, is a 14.5 kDa protein consisting of 140 amino acids encoded by 5 exons and having a transcript length of 3041bps. Located on 4q21.3-q22 of human chromosome 4, this synuclein protein family also includes SNCB (5q35) and SNCG (10q23.2-q23.3). The structure of SNCA protein comprises an N-terminal region with incomplete KXKEGV motifs, an extremely hydrophobic NAC domain, and an acidic C-terminal domain. Under physiological conditions, it appears as either an intrinsically disordered monomer or helically folded tetramer structure. Although it was previously thought to be toxic in this form, recent observations have refuted this idea. Over the last two decades, various hypotheses have been put forward regarding the toxic structural form of SNCA; none has yet been unanimously agreed upon. What is known is that its neurotoxic form accumulates within neurons before disseminating throughout anatomically interconnected regions in the Parkinson’s disease brain through interneural transmission using various mechanisms. Although SNCA is most abundantly expressed in the brain, it also appears in heart, skeletal, muscle, and pancreas cells. While its exact function remains undetermined, several hypotheses have been proposed based on its structure, physical properties, and interactions with interacting partners. SNCA may play an essential role in regulating dopamine release and transport, inducing microtubule-associated protein tau fibrillization and exerting a neuroprotective phenotype in non-dopaminergic neurons by modulating both p53 expression and transactivation of proapoptotic genes leading to decreased caspase-3 activation. Given SNCA’s central role in neurodegenerative processes, its essentiality may suggest that selective forces among sarcopterygians play a vital role in modulating its molecular and cellular mechanisms. Fine-tuning of these mechanisms through minute changes to protein activity could have contributed to evolutionary adaptations that meet different environmental and ecological needs. Current evidence indicates that amino acids 32 to 58 of SNCA’s N-terminal lipid binding domain are critical to its normal cellular functioning and disease pathogenesis. Lineage-specific substitutions could have led to structural remodeling and functional adaptation in SNCA over generations, and any mutation affecting its critical regions is likely to be harmful. These discoveries provide the framework for investigating their critical roles through various interaction studies as well as targeting them with drug discovery efforts to treat FPD ^[5]. Mutations in LRRK2 account for 5–12% of familial parkinsonism cases and 1–5% of sporadic cases. So far, seven missense LRRK2 mutations have been identified as pathogenic: R1441G, R1441C, and R1441H were all found to be pathogenic; these variants can be found within different functional domains of LRRK2, including R1441G located on R1441C, which affects R1441H; Y1699C was also involved, as well G2019S, R1628P, G2385R, and I2020T variants specific to certain populations. The G2019S mutation, which leads to constitutive activation of the kinase, is one of the most prevalent. It accounts for an estimated 36% of familial and sporadic Parkinson’s cases among North African Arabs; approximately 30% among Ashkenazi Jewish populations; up to 6% among familial cases in Europe and North America; and up to 3% among apparently sporadic cases; however, it does not occur among Asian populations. Various other LRRK2 mutations such as G2385R, R1628P, S1647T, R1398H, and N551K have also been associated with parkinsonism within certain Asian populations. Studies conducted among Asian populations spanning Singapore, Taiwan, and mainland China have established that LRRK2 variants G2385R or R1628P may increase risk for Parkinson disease. Furthermore, the G2385R variant has been found to increase risk for Parkinson’s disease among Japanese and Korean populations; these variants were not seen among Indians and Caucasians. Although LRRK2 mutations exist in familial PD, no differences exist in clinical features or neurochemical differentiation between idiopathic and familial forms of parkinsonism. Both forms of Parkinson disease (PD) involve profound dopaminergic neuronal degeneration and gliosis in the SNpc, decreased dopamine levels in the caudate putamen, and Lewy body pathology in the brainstem; therefore, understanding LRRK2 plays an essential role for all forms of PD ^[6]. Mutations in the PINK1 gene are an important cause of early-onset Parkinson’s disease (EOPD), accounting for 1–9% of genetic cases and 15% of early-onset cases—second only to Parkin mutations. First identified by Unoki and Nakamura in 2001, its 18 Kb span contains 8 exonic regions that encode for an essential serine/threonine protein kinase essential for mitochondrial functioning and metabolism. As reported by the MDSGene database, worldwide there have been 151 PINK1 mutation carriers who carry 62 different disease-causing sequence variants involved with both sporadic and familial Parkinson disease cases; 13 definitely pathogenic mutations exist alongside 44 possibly pathogenic variants (13 definitely pathogenic mutations and 44 possibly pathogenic variants). PINK1, an encoded protein from the PINK1 gene, primarily localizes to mitochondria where it serves as a serine/threonine-type protein kinase that regulates mitochondrial quality control (mitoQC). MitoQC involves maintaining respiring mitochondrial networks while selectively eliminating damaged ones through mitophagy, an essential process critical for cell homeostasis. Furthermore, in addition to mitoQC functions, PINK1 also plays an anti-death, pro-survival role under various forms of stress conditions, preventing neuronal cell death under various stress conditions. Additionally, its protein contains an N-terminal mitochondrial targeting sequence (MTS or TMD), transmembrane sequence (TMS or TMD), and C-terminal domain ^[7].

2. Perspectives of Treatment

The metal-based hypothesis of neurodegeneration is an attractive explanation for the pathophysiology behind Parkinson’s disease. This hypothesis proposes that reactive oxygen species are generated by redox-active metals, particularly iron. ROS (reactive oxygen species) cause membrane phospholipids to be peroxidized, resulting in the production of reactive aldehydes. Both ROS and reactive aldehydes modify α-synuclein, causing it to aggregate. Aggregated α-synuclein causes mitochondrial dysfunction, resulting in a vicious cycle of increased ROS production and decreased ATP synthesis. In order to provide a more effective treatment of PD, a multi-task strategy targeting these events is needed ^[8]. Coenzyme Q10 is a vital antioxidant that is important in reducing oxidative stresses, a factor implicated in Parkinson’s disease and other neurodegenerative diseases. In order to establish their potential as a marker of disease, a number of studies have investigated the levels of CoQ10 found in different tissues of people with PD or other parkinsonian disorders. Several studies have also explored the therapeutic potential of CoQ10 for the treatment of PD or PS. Several clinical studies have examined the ability of ubiquinol (the antioxidant form of Coenzyme 10 or CoQ10) to reduce oxidative damages observed in PD. CoQ10 can restore mitochondrial function by bypassing Complex I dysfunction, which is a feature of sporadic PD. A meta-analysis consisting of 8 controlled trials involving 899 patients found that CoQ10 is well-tolerated, safe, and does not improve motor symptoms compared to placebo. The study authors do not recommend CoQ10 as a routine treatment for PD except in cases where levodopa is wearing off ^[9]. Recent clinical trials have shown that iron chelation therapy is a promising approach to treating Parkinson’s disease. Due to the multifactorial nature of PD, targeting a specific factor, such as iron, may not be enough for complete neuroprotection. It may be necessary to develop and test multifunctional drugs that combine the iron chelation process with other protective properties. A growing global population is aging, and central nervous system disorders such as Parkinson’s and Alzheimer’s diseases are becoming more prevalent. These disorders are linked to iron accumulation in certain areas of the mind. Finding effective treatments for these conditions is therefore crucial to improving the longevity and quality of life of elderly people ^[10]. DFO (deferrioxamine) was administered intramuscularly in early studies of Alzheimer’s patients. DFP (deferiprone) was the first oral chelator used to treat Friedreich’s Ataxia ^[11]. This condition is characterized by frataxin deficiency, which is the mitochondrial chaperone for iron. Animal studies have shown that DFO or DFP can reduce iron in different brain regions, and also provide neuroprotection for an animal model of Parkinson’s disease. In two clinical trials, oral DFP was administered to PD patients in cohorts. MRI measurements showed that the iron content of the substantia nigra, as measured by DFP, decreased. UPDRS scores also improved. Iron chelation was not effective in patients who had high levels of inflammatory marker IL-6. DFP has a major problem with agranulocytosis, and neutropenia. This requires testing of white blood counts every week and complicates logistics. DFP is currently being tested in phase II clinical trials on early-stage PD ^[8][12]. α-Synuclein is another point of interest regarding the treatment of PD. Although clinical trials using monoclonal antibodies to treat α-synuclein aggregates have failed to show any improvement in Parkinson’s symptoms, other studies in progress or recruiting participants may prove that targeting α-synucleinopathies as a therapeutic option is possible.