Druggable targets for Parkinson’s disease: An overview

. One of the most crippling conditions affecting the brain and its progression causes neurodegeneration is Parkinson's disease (PD). The disease is characterized by accumulation of α -synuclein having Lewy bodies and further loss of dopaminergic neuron in substantia nigra, ultimately causing reduced ability of voluntary movements. The main symptoms of PD include tremor, bradykinesia and rigidity. Though, various symptomatic treatment options are available targeting both motor and non-motor signs but none of them claim to improve quality of life of PD patients. Recent studies indicated the identification of targets for PD such as glutamate receptors, α -Syn, c-Abl, molecular chaperones, GPR109Aand metals have been and some drugs targeting these targets are already there in market. The effectiveness of these pharmacological targets in treating PD has to be confirmed by a larger-scale trial. Effective PD therapy may also target pathways mediated by autophagy. Gene therapy and gene editing all have strong therapeutic effects and provide fresh PD medication targets. Additionally, the therapy of PD is more effective when a multi-target response is used. Further, research should be conducted to validate and explore new targets for treatment ofPD.


Introduction
Parkinson's disease (PD) is a neurodegenerative disease that belongs to synucleinopathy (a class of neurodegenerative conditions marked by an aberrant buildup of soluble -synuclein in glial and neuronal cells), which gradually develops, and there's not any good a technique for early detection and treatment.PD is a brain disorder that causes uncontrollable movements or unintended, such as stiffness, shaking and difficulty with balance and coordination.Over time, this disease becomes worsen and more worsen.Many people have difficulties in walking as well as talking as this disease progresses.Mental behavior changes, depression, sleep problems, fatigue and memory difficulties are some common problems in PD.Mostly PD can occur at elderly age and some of the researches also show that elderly men have been more in PD than elderly women.PD can be inherited or can be from genetic mutations.Parkinson's symptoms and indicators can include tremor, bradykinesia, tight muscles, poor posture and balance, loss of automatic motions, changes in speech and writing, and tremor.Druggable targets have been used to assess the potential for pharmacological activity on a novel, predicted protein from the genome.GPCR families, protein kinases, and several enzymes are notable instances of this.[1-2].

Prevalence
There are 1-2 cases of PD for every 1000 people, however; PD prevalence rises with age and affects 1% of those over the age of 60.More people worldwide are becoming disabled and dying from Parkinson's disease (PD) than from any other neurological condition.In the last 25 years, PD prevalence has doubled.According to 2019 estimates, there were approximately 8.5 million people worldwide who had PD.According to estimates, PD caused 329 000 deaths in 2019, a rise of over 100% since 2000, and 5.8 million disability-adjusted life years, an increase of 81% since 2000.The rise in Estimates of PD prevalence highlight the growing personal and societal burden and the urgent need for actions to tackle and have an influence on this difficult disease[3].

Symptoms
Lewy bodies containing α-Syn and dopaminergic neuron loss in the substantia nigra, which manifests as lessened facilitation of voluntary movements, are the primary neuropathological findings.As PD worsens, Lewy body disease spreads to the cortex and neocortex.The three primary signs of Parkinson's disease are tremor, rigidity, and bradykinesia.Postural instability is no longer included as a fourth characteristic in the diagnostic criteria, which also describe supporting criteria, absolute exclusion criteria, and red flags [4].
In PD, non-motor symptoms are receiving more attention, and both motor and non-motor symptoms are now considered supportive criteria.In most situations, the cause of PD is unknown.There are known genetic risk factors, such as uncommon monogenetic causes in populations without selection.In 5-10% of patients, a genetic component can be detected.There are several environmental factors linked to an increased risk of PD.According to studies on corpses, a significant number of people do not have their Parkinson's disease clinical diagnosis verified during autopsies.The accuracy of the clinician's diagnosis of PD is anticipated to increase with the revised diagnostic criteria.In the near future, it's likely that growing awareness of the genetic and environmental PD risk factors may reveal the disease's underlying cause [4].

Drug Targets forPD 1 Glutamate Receptors
Glutamate receptors have ability of controlled neural transmission in basal ganglia in our brain.The targets of PD treatment can be also studied/identified with this ability of Glutamate receptors.By postponing the neurodegenerative processes, compounds that act against these receptors can slow the progression of PD.Neuroprotection is a function of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors.Additionally, levodopa-induced dyskinesias (Uncontrolled, involuntary movements of the face, arms or legs) can be effectively treated with its antagonist Perampanel.(mGluRs) Metabotropic glutamate receptors pharmacological modulation can regulate neurotransmission can help in delay PD.Some drugs that target glutamate receptors like antagonists of mGluR5, Motor dysfunctions can be treated, and activators of group II mGluRs and group II mGluR4 can prevent neurodegeneration that can help in delay progression of PD [5-6].

Alpha-synuclein(α-Syn)
The α-Syn protein is usually insoluble in blood, and in PD it gets accumulated and enhances the PD progression.The SNCA gene also encodes the -Syn protein.Further, it has been observed that the accumulation ultimately causes the LBD (disease associated with abnormal deposits of a protein).The α-Syn protein despite having the appropriate mechanism, experiences point mutations, triplications, and duplications of α-Syn protein in PD is still unknown.Oligomerization (a chemical procedure that, through a limited amount of polymerization, transforms monomers into macromolecular complexes) of α-Syn form toxic add on which multiplies from one to another cell.The development of -Syn protein's harmful effects can be prevented in four ways that have been identified and documented so far i.e.; reducing α-Syn aggregation, boosting its clearance, limiting its multiplication, and stabilizing its current situation.The aggregation of α-Syn protein has been recorded to extend to the cell types and cell populations in brain.And two key mechanisms-autophagy and the (UPS) ubiquitin-proteasome system-have been implicated in reaching different types and populations of brain cells.UPS also degrades the proteins so thus it can also degrade α-Syn protein and can enhance the PD pathogenesis.Using both inherent and learned immunity, By reducing inflammation brought on by α-Syn protein and proteotoxic processes, the clearance of pathogenic aggregates can be increased [10][11][12][13][14].
Some methods (related to α-Syn protein) to induce progress slowly of PD are by immunotherapy aggregation of the α-Syn can be suppressed, Motor impairments can be restored by preventing the creation of the α-Syn axonal, Antibodies that prevent C terminal truncation can reduce α-Syn protein cell-to-cell proliferation, Oxidation and nitration are further processes that can be used to degrade the aggregation of α-Syn protein of α-Syn protein and these oxidation and nitration of α-Syn protein can also block oligomerization.Some of these methods are still in validation process but apart from that all the above methods have already showed lesser aggregation of α-Syn protein in PD patients [15].

GeneTherapy
Disease-modifying and non-disease-modifying transgene levels in gene therapy has revealed convincing results for PD treatment in both animals and people.Some of the factors that halts the progression of PD at preclinical level are cerebral dopamine neurotrophic factor, Growth derived neurotrophic factor, brain-derived neurotrophic factor, and nurturing.Mutations in mitochondrial genes are also to blame for the development of Parkinson's disease.A potential gene treatment for Parkinson's disease (PD) involves targeting certain mitochondrial genes, such as Parkin and Pink1, which result in decreased activity of the electron transport system, abnormal mitochondrial dynamics, impaired mitochondrial permeability, and altered membrane potential.Clinical studies have also demonstrated an association between α-Syn buildup and decreased miR-7 levels.The gene therapy that substitutes for miR-7 activity also slows the onset of PD [16][17][18][19].

Gene Editing
The clustered regularly interspaced short palindromic repeats (CRISPR) technology is particularly useful for discovering fresh PD research pathways and gene-gene interactions.In addition to greatly reducing oxidative stress and neuroinflammatory load, the CRISPR-Cas9 gene editing method also significantly reduced the progression of Parkinson's disease (PD).A valuable method for identifying and tracking dopaminergic neuronal defects is CRISPR/Cas9-mediated gene editing.It may also be useful for creating knockout cell lines that may be used to more thoroughly study illness.Therefore, Gene editing might also carry potential treatment for the PD [20][21][22][23].

Metals
Researchers discovered connections between metals and PD.[24][25][26] On the one hand, because they can result in neuronal death through oxidative stress, metals, particularly heavy metals, are typically viewed as neurotoxins.[27] For instance, both copper and iron can lead to oxidative stress and harm neurocytes, Both the both the periphery and the central nervous systems experience substantial swelling and neuronal death as a result of lead exposure, PD patients have considerably more aluminum than controls in their substantia nigra, Cerium has been shown to have a detrimental impact on DNA methylation, i.e., cerium is likely to cause PD. [28] Cerium oxide nanoparticles (CeO2 NPs), a different cerium chemical, have shown promising results and may be able to treat several neurological illnesses, including Parkinson's disease.
[29] People are reasonably knowledgeable on the pathophysiology of various metals.[30]On the other hand, current research has revealed that metals can control epigenetics in Parkinson's disease.Finding a cure for PD maybe aided by understanding the functions that metals play in the epigenetics of the disease [31].A larger-scale trial is required to confirm whether these pharmaceutical targets are useful in treating PD.Effective PD therapy may also target pathways mediated by autophagy.Gene therapy and gene editing all have strong therapeutic effects and provide fresh PD medication targets.Additionally, the therapy of PD is more effective when a multi-target response is used.Further, research should be conducted to validate and explore new targets for treatment ofPD.[3] https://www.who.
Multiple α-Syn oligomers cause damage to specific areas of the brain in PD [7-9].

Table 1
Some heavy metals and their role in PD with their respective targets [2