INTRODUCTION:

Parkinson disease (PD) is the mutual physical movement disorder, and it is 2^nd most progressive widespread neurodegenerative disorder all over the world, and it is reported that and essential 10 million, over 0.3 % of the total world population. PD is measured by (i) The impairment of thirteen dopaminergic neurons in substantia nigra pars compacta leading 14 to reduced dopamine levels in the basal ganglia (ii) the 15 building of Lewy bodies–intracytoplasmic embellishments containing 16 fibrillar a-synuclein.^{1,
2, 3, 10}

A thoughtful reduction of the neurotransmitter dopamine (DA) in the striatum is the main cause of these motor symptoms, collectively known as parkinsonism². In parkinsonism, dysregulation is mostly caused by the loss of dopamine in basal ganglia ensuing in key clinical motor symptoms including Brady-kinesia, Resting-tremor, Inflexibility and Postural rest ability to this some of non-motor symptoms such as Sleep disorders, Depression, Cerebral deficits, Physical dysfunction.¹

The parkinsonism include dementia with lewy bodies (DLB), corticobasal degeneration (CBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP).

Mitochondria serves as most important organelle in most of the cells and are essential for life and it is also called as heart for all cellular metabolism. The main and most important role of mitochondria is generation of ATP via oxidative phosphorylation^12,5. As we all know that neurons have a high energy mandate and are mostly powered by mitochondria and defective mitochondria supply insufficient energy leading to neuronal death and neuro inflammation and therefore decrease in brain energy metabolism and glucose uptake are informed as pathogenesis of neurodegenerative disease^1,2,5,12. In this study we are going to discuss the deficiency of complex Ⅰ and we are going to see how Parkinson disease occurs due to familial and sporadic Parkinson disease and also the emerging therapeutic strategies for mitochondrial dysfunction in Parkinson disease.

Mitochondrial complex and oxidative stress in PD

Mitochondria complex Ⅰ (NADH Quinone oxidoreductase) deficiency

The straightforward relation among mitochondrial dysfunction and Parkinson disease came from the autopsy description of complex Ⅰ in the substantia nigra of subjects or patients with PD and animal model of PD which has been developed by injecting MPTP (1-methyl-4- phenyl-1,2,3,6–tetrahydropyridine)^1,2,8. The cruelty of this deficiency in complex Ⅰ activity described in the substantia nigra of PD patients and animal study or animal model communicates to about 35% reduction compared to control population.^2,8

A most important development in a study of pathogenic mechanism fundamental PD came from specific cases of induced parkinsonism in California in 1980 ‘s. A drug injected themselves with the synthetic heroine analogue MPTP and with in days of injecting MPTP injection developed PD and autopsy report or analysis revealed significant lesions of Dopaminergic neuron in substantia nigra pars compacta (SNpc). And in an mitochondrial DNA (mtDNA) mutations causes a documented deficits in complex Ⅰ and a neurodegenerative phenotype such as in leber, s optic atropy.^1,2

From the study of above MPTP animal model it has been observed that a blockade of complex Ⅰ kills cells via a recruitment of the Mitochondria-dependent apoptotic pathway. After the study the isolated brain mitochondria complex Ⅰ dysfunction caused by either pharmacological or genetic means fails to directly activate this cell death pathway and to kill cells. Shortly following the discovery of parkinsonism caused by MPTP administration. It was reported that complex Ⅰ activity is decreased in the SNpc in PD patients. In an specific animal study like the Retenone model suggests that a mild systemic impairment of mitochondrial complex Ⅰ is sufficient to cause many of the pathological and behavioural symbol of PD in mammals.^1,2,8

Molecular mechanism underlying complex Ⅰ deficiency in Parkinson disease

As we all know that mitochondrial complex Ⅰ deficiency occurs in the substantia nigra of individuals and mostly this is phenomenon is caused by collecting mitochondrial DNA damage in neurons and that it contributes to process of neurodegeneration. These complex Ⅰ deficiency expanded beyond the substantia nigra to other effected brain region in PD and connect securely with neuronal mtDNA damage.²

Even Though many studies are acknowledging that there is a complex Ⅰ defect in the mitochondria from Parkinson disease patient role. Here are many prospects they all couldn’t explain the complex Ⅰ deficiency In the PD by MPTP animal model and verified absolute environmental cause of Parkinson disease. By monitoring many developed meta-analysis that merges gene expression of ten sets of genes varies between Parkinson and control dopaminergic SNpc cell isolated using less microdissections. The mitochondrial DNA is overlapped and codes for 13 protein coded by mitochondrial DNA include subunits from all parts of the electron transport chain within 6 of the genes coating for complex Ⅰ subunits hence point mutations or deletions in any of these 6-genes could viably alter complex Ⅰ activity. So several areas of evidence support the hypothesis that the complex Ⅰ defect observations in Parkinson disease is the original point mutations of the mitochondrial DNA.^2,5

Here an study has been made by transferring mitochondria of Parkinson diseased patient into the cells that has no mitochondrial DNA of its own and this type of cells are called cybrid cells, the complex Ⅰ deficiency is observed in resulting cells and very large numbers of studies have wanted to identify individual mitochondrial DNA point mutations associated with Parkinson disease but studies using large samples size have not proven difference between the mutational load of Parkinson disease patient and controls.²

Oxidative stress in Parkinson disease

The major source of reactive oxygen species (ROS) in eukaryotic cells are electron transport chain in the mitochondria, As inhibition of complex Ⅰ decrease mitochondrial ATP production and increase the formation of reactive oxygen species which has an enormous effect on mitochondrial DNA and other mitochondrial factors and causes or mostly responsible for mitochondrial impairment and oxidative stress.(2) So hence complex Ⅰ acts as the access point for electrons from the Mitochondrial matrix into the Electron Transport Chain by catalysing the electro transport from NADH into the subunits of Electron Transport Chain.

In the Electron transport chain Complex-Ⅰ and Complex -Ⅲ (at some minor quantity) are refereed to be the main area of reactive oxygen species making in the mitochondria (2). Inside the mitochondria superoxide is converted into hydrogen peroxide in the presence of enzyme called manganese superoxide dismutase and with some other enzymes responsible for the process in the mitochondria and catalyses further for reduction of hydrogen peroxides to water and molecular oxygen. Reactive oxygen species production to exceed the antioxidant capacity of a cell this condition termed oxidative stress. Which causes long-lasting damage to cellular macromolecules and can eventually lead to cell death. Enhanced stress resulting from reactive oxygen species construction is one of the proposed mechanisms in Parkinson disease and Mitochondrial complex Ⅰ for the expiry of Dopaminergic neurons which is considered to be one of the leading source of reactive oxygen species. Evidence that oxidative stress as a result of mitochondrial dysfunction is enhanced in the brain tissue of patients with Parkinson disease is exciting but it is debatable whether it occurs early or later during the death of neurons^1,2,3,8.

Mitochondrial Dysfunction in Parkinson disease

Mitochondrial dysfunction is projected to be hallmark to the pathogenesis of both sporadic and familial Parkinson disease, observed from experimental model and human Parkinson disease provide strong sign for interruptions in complex inhibition of the electron transport chain and increase reactive oxygen species.¹³

Mitochondrial Dysfunction in familial Parkinson disease

At some amount till today and at present few gene have been acknowledged as Monogenic cause of familial Parkinson disease with many of the pathogenic mutations where genes are directly attached to mitochondrial dysfunction and these genes which are attached- autosomal dominant SNCA and RRk2 mutations and autosomal recessive parkin, AYP13A2 mutations, vacolar protein sorting associated protein-35 (VPS-35), coiled-coil-helix-coiled-coil-helix-2 (CHCHD2), and leucine rich repeat kinase-2 domain containing-2 (LRRK-2).^{4, 15}

Mitochondrial dysfunction in sporadic Parkinson’s disease

Sporadic Parkinson disease mainly and frequently occurs mainly due to undefined genetic bases in the absence of an evident family history. Roughly influenced Cellular paths include Proteostasis, Oxidative Stress and the multiple paths relating to Mitochondrial function. Basically, these all are underlined proof for the pathogenesis of sporadic Parkinson disease and these is an huge contribution or sharing of genetic and environmental influence on sporadic Parkinson disease. Some phenotypes consisting the sporadic Parkinson disease can be induced by mitochondrial function mainly by exogeneous and endogenous inhibitors. Which may mostly include rotenone, MPTP, paraquat nitric oxide, the dopamine metabolises amino-chrome and others.^{4, 8}

From a genetic prospective genome all the study about this sporadic Parkinson disease were obtained from genome wide association studies (GWAS) and has provided evidence that polymorphism in familial Parkinson disease genes are risk factor for developing sporadic Parkinson disease and alpha-synuclein is an hallmark of neuronal degeneration in sporadic Parkinson disease because alpha-synuclein has identified that it binds to Outer Membrane Mitochondrial proteins which are VDAC-1 (voltage dependent anion selective channel-Ⅰ) Translocase of Outer Membrane-20 and 40 (TOM-20 and TOM-40). Sporadic Parkinson disease patient nigral neurons in association with alpha-synuclein groups and is consequently incriminated as a component of overall mitochondrial dysfunction in sporadic Parkinson disease.^4,8

Emerging therapeutic strategies

Parkinson disease is a neurodegenerative disease like other, which almost causes socioeconomic and emotional breakdown of the patient effect with Parkinson disease. Rendering to the various research studies and animal model experiment mitochondrial dysfunction is the appealing target for the enhancement of drug or medication for treatment.

So, here improving or targeting the mitochondrial function in both familial and sporadic Parkinson disease gives an good improvement in the treatment of Parkinson disease. Non-clinical activated mitophagy can provide an alternative pathway in Parkinson disease to restore Mitochondria function in several proteins such as FUN-14 domain containing protein (FUNDC1) and autophagy and beclin-1 regulator displayed an ability to modulate mitophagy in PINK-1/Parkin independent manner^4,16. So another way for good conditioning of mitochondria is replace neurons by increasing mitochondrial biogenesis, dimethyl fumarate or BG-12 been effective in some phases of clinical trials for degenerating multiple sclerosis and approved for treating patients^4,17.

Targeting antioxidants and flavonoids in mitochondria have show promising result in animal model for neurodegeneration and migrate mitochondrial dysfunction using antioxidants have produced positive results in preclinical studies also. Coenzyme Q10 is an important antioxidant familiar in the mitochondria and lipid membrane it is an one of the endogenous compound which is lipid soluble or component of electro transport chain which serves as a co-factor by accepting electrons from Complex Ⅰ-Ⅱ and Ⅲ. And by observing several research study administration of coenzyme Q10 clearly indicates its potential as promising therapeutic drug for Parkinson disease due to mitochondrial dysfunction^4,14.

Another approach for treating Parkinson disease by cell transplant therapy, transplant of neuronal stem cell into the brain of Parkinson diseased patient is considered to be on of the most capable approach for treating this disease mostly by transplant of dopamine cells such as into the striata in animal model of Parkinson disease. Also some clinical benefits are also observed in allogenic human fetal ventral mesencephalic tissue transplantation in Parkinson diseased patients, so these cells survive and increase dopamine levels within the host cells. Further research is needed to evaluate the safety and efficacy of stem cells therapy before it can be approved as a treatment of human Parkinson diseased patients^9,18.

Prospects of the study:

There are various studies has been developed and conducted using an genetic and toxin models of Parkinson disease to know pathogenesis of the disease. How the complex Ⅰ deficiency is responsible for oxidative stress and reactive oxygen species and leads to mitochondrial dysfunction in cell and lipid layers of the cell. So still some studies are going and it helps in finding the factors that potentially causes mitochondrial damage in sporadic Parkinson disease because its still unknow how it occurs. So in future research its an challenging to researchers to find how a sporadic Parkinson occurs in Parkinson diseased patient.

And this study also leads to study of mitochondrial dysfunction and oxidative stress underline extranigral pathology of Parkinson disease and this leads to future research to therapeutic advances for Parkinson disease and parkinsonism.

ACKNOWLEDGEMENT:

All the above data were reviewed and analyse from the different research and reviewed clinical studies and this all credits and regards goes to all authors and papers which I have referred for this review article.

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Received on 05.06.2021 Modified on 19.08.2021

Res. J. Pharmacology and Pharmacodynamics.2021;13(4):167-170.

DOI: 10.52711/2321-5836.2021.00031