Neurodegenerative Diseases: Multifactorial Degenerative Processes, Biomarkers and Therapeutic Approaches

By Tabish Qidwai

This reference is the definitive guide to common neurodegenerative diseases that affect humans. The book covers mechanisms of some of the most well-known neurodegenerative diseases, their biomarkers, neuropharmacology, and emerging treatment strategies.

The book introduces the subject of neurodegeneration by outlining the biochemistry, pathophysiology and multifactorial neurological mechanisms (the role of genetics, environmental factors and mitochondrial damage, for example). Next, it explains some of the most studied diseases, namely, Parkinson’s Disease, Alzheimer’s Disease, Huntington’s Disease, and Multiple Sclerosis. Subsequent chapters delve into current knowledge about diagnostic and immunological biomarkers, followed by a summary of novel therapeutic strategies.

Special attention has been given to the role of medicinal plants in attempting to treat neurodegenerative diseases, as well as the public health burden posed by these conditions.

Key Features

- give readers an overview of multifactorial disease mechanisms in neurodegeneration

- covers some major neurodegenerative diseases in detail

- covers diagnostic and immunological biomarkers

- explores current therapeutic strategies and drug targets in common neurodegenerative diseases

- offers a simple presentation with references for advanced readers

The book is a suitable reference for all readers, including students, research scholars, and physicians who are interested in the mechanisms and treatment of neurodegenerative diseases.

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Aug 10, 2022
• ISBN: 9789815040913

Tabish Qidwai

Dr. Tabish Qidwai PhD is currently an Associate Professor and part of the Faculty of Biotechnology, IBST, Shriramswaroop Memorial University, Lucknow in India. Dr. Qidai pre-doctoral and doctoral research was at CSIR-CIMAP & UP Technical University Lucknow from 2008-2013. He studied host polymorphism in genes related to Plasmodium falciparum infection in an endemic region of India and later worked on the identification and characterization of antimalarial drug targets in Plasmodium falciparum. His postdoctoral research from 2-14-2018 at Babasaheb Bhimrao Ambedkar University, Lucknow explored compounds as potential antimalarial against Plasmodium falciparum. Dr. Qidwai has published over 30 journal articles, contributed book chapters, and recently published a book on Exploration of Host Genetic Factors associated with Malaria. He is a Life member of Society of Biological Chemists, India, the Indian Biophysical Society, and the Indian Science Congress Association. He is also a Member of the International Association of Engineers (IAENG) and the International Society for Infectious Diseases.

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Neurodegenerative Diseases Involve Multifactorial Interplay of Genetics and Environmental Factors

Tabish Qidwai¹, *

¹ Faculty of Biotechnology, IBST, Shri Ramswaroop Memorial University, Lucknow-Deva Road, UP, India

Abstract

Neurodegenerative diseases are one of the leading causes of morbidity and disability worldwide, afflicting millions of individuals. These diseases emerge as a result of multiple factors, sharing pathogenic pathway that includes mitochondrial dysfunction, misfolded protein aggregation, and oxidative stress. Genetic and environmental factors have been identified to play a key role in neurodegeneration and modifying the risk of the disease. The association of neurodegenerative diseases to genetic factors and environmental agent’s exposure is not well conclusive. As a consequence, studying the interplay of genetic and environmental factors in neurodegenerative diseases can help researchers better understand gene and therapy and disease progression. In this chapter, an attempt has been made to discuss the multifactorial degenerative process and the role of genetic and environmental factors in common neurodegenerative diseases. Understanding the mechanisms of disease initiation and progression is crucial for disease prevention and modification of disease risk. These information would be helpful in the exploration of therapeutic options against these diseases.

Keywords: Environmental factors, Genetic factors, Multifactorial, Mitochondrial dysfunction, Neurodegenerative diseases, Protein aggregation, Reactive oxygen species, Risk of disease, Therapeutics.

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* Corresponding author Tabish Qidwai: Faculty of Biotechnology, IBST, Shri Ramswaroop Memorial University, Lucknow-Deva Road, Barabanki, UP, India; Tel: [phone]; E-mail: [e-mail]

INTRODUCTION

Neurodegenerative diseases are the leading cause of morbidity and disability. Researchers are giving special attention to these diseases as they impose a considerable socioeconomic impact. Millions of people throughout the world suffer from neurodegenerative diseases. Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are all common neurodegenerative diseases. These diseases result in a variety of

illnesses with varied etiologies and morphological and pathophysiological characteristics. The most commonly reported neurodegenerative diseases are Alzheimer's and Parkinson's diseases, which rank first and second, respectively, among neurodegenerative diseases. Over the course of its five-year plan, the World Health Organization (WHO) has adopted a specific push for Mental Health, with the goal of increasing treatment coverage for mental health problems for one hundred million additional individuals [1]. It has been identified that abnormal protein dynamics, including incorrect protein breakdown and aggregation, oxidative stress and free radical formation, bioenergetic impairment, and mitochondrial malfunction are all factors that contribute to neurodegenerative diseases. Aggregation and deposition of misfolded proteins, oxidative stress and mitochondrial dysfunction cause deterioration of the central nervous system [2].

Neurodegenerative disorders are multifactorial disorders including the interplay of aging, genetics and environmental factors. Genetic and environmental factors have been shown to play a key role in neurodegenerative diseases. The role of genetic factors is central to the etiology of neurodegeneration. Identification of disease genes and risk loci has contributed a lot to medicine. Genome wide association studies have increased our knowledge of the genome and the genetics of neurodegenerative disease. Studies have identified that genetics is targeting to find new disease-modifying therapies for neurodegenerative diseases. Certain genetic polymorphisms and increasing age are identified as risk factors for neurodegenerative disease. Other likely reasons might comprise gender, oxidative stress, inflammation, stroke, hypertension, diabetes, smoking, head trauma, and chemical exposure. In addition to this, exposure to metal toxicity and pesticides are responsible for the appearance of neurodegenerative diseases, we should focus on environmental factors in these diseases [3]. The pathogenesis of many of these diseases remains unknown. The association between environmental agent’s exposure and neurodegenerative diseases is not well explored and conclusive. Besides, the role of genetic factors in neurodegenerative diseases is not investigated quite well. Exploration of genetic factors and environmental factors would be important in the identification of risk factors and effective therapeutics in neurodegenerative diseases. This chapter covers the genetic and environmental factors associated with neurodegenerative diseases. Moreover, the multifactorial nature of diseases has been covered.

NEURODEGENERATIVE DISEASES INVOLVING MULTIFACTORIAL DEGENERATION

Neurodegenerative diseases such as AD, PD, HD and ALS, etc. are multifactorial in nature. They rely on a common pathogenetic mechanism involving aggregation and deposition of misfolded proteins, oxidative stress and mitochondrial dysfunction leading to the deterioration of the central nervous system [2]. Identification of the basic etiology of these diseases would be important in therapies against them. Despite the fact that each disease has its own molecular mechanism and clinical manifestations, several common pathways may be found in various pathogenic cascades [2]. Neurodegenerative diseases are multifactorial degenerative process, hence interplay of several factors have been evidenced (Fig. 1). Misfolding and non-functional protein trafficking are the causes of diseases including Alzheimer's, Parkinson's, and Huntington's. Moreover, mitochondrial dysfunction, oxidative stress, and/or environmental factors have shown a strong association with age implicated in neurodegeneration. Mutations in several human genes have been associated to neurodegenerative diseases.

Fig. (1))

This Fig represents the factors associated with neurodegenerative diseases.

Protein Misfolding and Aggregation in Neurodegenerative Diseases

Stable conformation of the protein is necessary for the biological function of the protein. Protein folding is a complex process, guided by a molecular chaperone. Protein folding is linked to gene transcription, protein biosynthesis, post-translational modifications, ubiquitin-proteasome system destruction, and autophagy. Disturbance in protein homeostasis will lead to protein misfolding this is the pathogenic underpinning of the most neurodegenerative diseases. Misfolded proteins frequently aggregate and accumulate, producing neurotoxicity and causing neurodegenerative diseases [3, 4].

Mitochondrial Dysfunction in Neurodegenerative Diseases

Cell death is a key feature of neurodegenerative diseases which is centrally regulated by the mitochondria. A key role of mitochondria has been identified in ageing-related neurodegenerative diseases [4]. Mitochondrial DNA mutation and oxidative stress contribute to ageing, which is one of the key risk factors for neurodegenerative diseases [5]. Impaired mitochondrial dynamics such as shape, size, fission-fusion, distribution, movement etc. have been detected in PD, HD, AD and ALS [6].

Mitophagy is a word used to refer to the reduction in mitochondrial biogenesis as a result of alterations in mitochondrial fission and fusion, as well as a decrease in the elimination of malfunctioning mitochondria, as the ageing process progresses [7]. Aging results in the accumulation of mutant proteins and mitochondrial abnormalities, leading to both functional and structural changes in neuronal activity and finally cell death (Fig. 2) [8].

Fig. (2))

Role of mitochondrial dysfunction in neurodegenerative diseases [8].

Reactive Oxygen Species (ROS) Production and Neurodegeneration

Neurodegenerative illnesses have been linked to excessive production of reactive oxygen species (ROS). Studies have been carried out to analyze the impact of ROS on neurodegenerative diseases [9]. The role of mitochondria is to provide ATP. In the absence of effective oxidative phosphorylation, there is a production of ROS, leading to mitochondrial dysfunction. Metabolisms in mitochondria potentially contribute free radicals. ROS has been proven to serve a dual role: a low level of ROS is needed for normal cell signalling, but a high level of ROS and long-term exposure causes damage to cellular components such as DNA, lipids, and proteins, resulting in necrosis and apoptotic cell death [10].

Because the brain requires a lot of oxygen and has a lot of lipids, it produces a lot of ROS, making it vulnerable to oxidative stress. Moreover, the membrane of a neuron contains a significant amount of polyunsaturated fatty acids, which are highly susceptible to reactive oxygen species (ROS). (Fig. 3). Various neurode- generative illnesses can be the result of biochemical alteration because of oxidative stress in biomolecular components. Malondialdehyde and 4-hydroxynonenal are oxidation products of polyunsaturated fatty acids, particularly arachidonic acid and docosahexanoic acid, which are prevalent in the brain. ROS damages proteins by oxidising the backbone and side chains, which then combines with amino acid side chains to produce carbonyl functionalities [11].

Fig. (3))

Reactive oxygen species (ROS) production and neuron damage.

GENETICS, ENVIRONMENTAL FACTORS AND INDUCTION OF NEURODEGENERATIVE DISEASES

Improvements in the health-care system have improved life expectancy in recent decades, and health-care advancements have led to people living longer, but this has also increased the number of people with chronic crippling conditions like Alzheimer's and Parkinson's disease. Researchers have identified that several endogenous/genetic and exogenous/environment factors play role in the onset and/or development of these illnesses. External factors including lifestyle and chemical exposures are linked with the risk of the onset of these diseases.

The role of genetic factors has been well investigated; approximately 5-10% of patients have familial PD due to Mendelian inheritance of genetic variants. Furthermore, genome-wide association studies (GWAS) have found common genetic variations that contribute to higher PD susceptibility [12].

A study has identified the contribution of individual loci to the pathogenesis of Alzheimer's disease however their precise involvement is unclear, so far [13]. Hence, application of genetic markers of disease, for monitoring development, time course, treatment response, and prognosis, is far away from clinical use.

GENETIC FACTORS ASSOCIATED WITH NEURODEGENERATIVE DISORDERS

Alzheimer’s Disease

Alzheimer's disease is the most common type of dementia in the elderly, accounting for 60-70 percent of cases. It is an incurable, progressing, and crippling disease [14]. The two types of Alzheimer's disease have been identified: familial/early onset Alzheimer's disease (EOAD) has been associated to particular gene mutations in the amyloid precursor protein (APP) and presenilin (PSEN) 1 and 2 genes, both of which are linked to the creation of amyloid beta (A) peptides [15]. EOAD develops in those under the age of 65 and accounts for 5% of all cases. Late-onset/sporadic AD (LOAD) is the most frequent form of Alzheimer's disease, accounting for 95% of all cases. Although genetic risk factors such as polymorphisms in the ApoE (coding apolipoprotein E), SORL1 (coding ApoE neuronal receptor), and GSK3 (coding glycogen synthase kinase 3 beta) genes have been suggested, this kind of AD is not caused by punctual mutations. Although the ApoE gene is the most powerful genetic risk factor for LOAD, it is insufficient to explain illness incidence [16].

One hypothesis suggests that overproduction of the amyloidbeta (Aβ) has been found. Neurofibrillary tangles (NFTs) are the outcome of the onset of amyloid deposits as Aβ plaques. Another theory proposes that the disease is caused by the hyperphosphorylation of the Tau protein and its subsequent deposition as NFTs. On the contrary, the overproduction of Aβ is caused by a reduction in the activity of ADAM10 (a desintegrin and metalloproteinase domain containing protein 10) [17]. Furthermore, a few mutations, such as those in PSEN1/PSEN2, can boost Aβ production [15].

Parkinson’s Disease

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's. According to some estimates, PD affects 1% of adults over the age of 60 [18]. The prevalence of PD is rising, posing healthcare challenges. The global prevalence of illness is expected to double from 62.2 million cases in 2015 to 121.9 million cases by 2040 [19]. Progressing age is the greatest risk factor for Parkinson’s disease, but both environment and genetics are thought to affect disease risk and progression. Although studying the environmental contribution to disease is complex, potential associations between Parkinson’s disease and several environmental traits have been found, including pesticide exposure, smoking, and caffeine intake [20-22].

The disease is multifactorial, hence exploring the interplay of genetic, environmental, hormonal factors could be important. Polymorphisms in inflammation related genes such as interleukins, chemokines have shown link with PD [23]. Genetic contributors to Parkinson’s disease exist across a continuum, ranging from DNA variants that are highly penetrant to variants that individually exert a small increase in lifetime risk of disease. Genetic risk is often divided into classes: rare DNA variants with high effect sizes, which are typically associated with monogenic or familial Parkinson’s disease; and more common, smaller effect variants, which are usually identified in seemingly sporadic Parkinson’s disease. Studies have suggested that mutations in more than 20 genes have been linked to disease, mostly they are extremely penetrant and often cause early onset or atypical symptoms [24]. Familial cases of Parkinson disease can be caused by mutations in LRRK2, PARK7, PINK1, PRKN and SNCA gene, or by changes in genes that have not been identified. Mutations in some of these genes may also play a key role in cases that appear to be sporadic (not inherited). Nearly, 50 epidemiological and 24 genomic studies and a genome-wide association studies (GWAS) have been done to identify the prevalence and penetrance of genes associated with PD [25]. Several genes have shown linkage to both autosomal dominant and recessive familial PD. But, only SNCA, LRRK2, VPS35, PRKN, PINK1, GBA and DJ-1 demonstrated convincing association with typical PD [26].

Huntington's Disease

Expansions of a repeat are a type of mutation resulting in abnormal repetition of certain DNA building blocks. This is very common in many neurological disorders. For instance, Huntington's disease occurs, when a sequence of three DNA building blocks that make up the gene for a protein called huntingtin repeats numerous times more than normal. These repeats can be used to predict whether someone will develop the illness. Huntingtin (HTT), present on chromosome 4 is mutated in exon-1 region, CAG repeat, which encodes polyglutamine (Fig. 4a). The higher the number of repeats in the gene, the earlier the onset of the disease (Fig. 4b).

Fig. (4a))

Pathological conditions arise due to abnormal repeats in Huntington's disease.

Fig. (4b))

Alteration in number of repeats associated with disease.

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease involving motor neuron degeneration in the spinal cord, brain stem and primary motor cortex. ALS can be inherited in three ways: autosomal dominant, autosomal recessive, or X-linked. According to some estimates, 90% of ALS cases are sporadic, with no evident genetic relationship; nevertheless, 10% of cases exhibit familial inheritance [27].

ENVIRONMENTAL FACTORS: ETIOLOGICAL AND DISEASE-MODIFYING EFFECTS ON DISEASES

Parkinson's disease is the second most common neurodegenerative disorder affecting many people over the age of 60 [18]. One study examined 66 meta-analyses that included 691 studies on environmental risk factors for Parkinson's disease. Six environmental factors have been identified as having a possible link in this study. Head injury, anxiety, sadness, and beta-blocker use all raise the risk of Parkinson's disease, but smoking, physical activity, and uric acid levels lower it [28]. Dairy products, pesticides, and traumatic brain damage were identified as risk factors, while smoking, coffee, urate, physical exercise, ibuprofen, and calcium channel blockers were identified as protective factors [29]. The most powerfully beneficial environmental factor connected to Parkinson's disease is cigarette smoking. It has been reported that active smokers had a 50% lower risk of Parkinson's disease than non-smokers [30]. Earlier studies revealed a link between passive smoking, smokeless tobacco usage, and Parkinson's disease [31-33].

Several factors have demonstrated association with AD, higher risk of AD is associated with pesticides, smoking, hypertension and high cholesterol levels in middle age, hyperhomocysteinaemia, traumatic brain injury and depression. A connection of AD with high aluminium intake in drinking water has been detected. Too much exposure to electromagnetic fields from electrical grids is associated with AD [34]. Toxic metals such as lead, aluminum, and cadmium showed association as they perturb metal homeostasis at the cellular and organismal levels [35]. These metals upset brain physiology and immunity, as well as their roles in the accumulation of toxic AD proteinaceous species for example beta-amyloid and tau. Environmental tobacco smoke was shown to be associated with dementia risk in a cross-sectional study of almost 6000 people in five provinces of China [36]. One cross-sectional study of 871 people in Taiwan also examined both particulate matter (PM 10) and ozone concentration at the participant’s home address, finding increased Alzheimer’s dementia risk in the second and third tertiles of PM10 concentrations [37]. Another study found that higher zinc levels in the soil are associated with an increased risk of Alzheimer’s dementia [38].

CONCLUDING REMARKS

Neurodegenerative diseases are affecting people worldwide. Researchers are being involved in extensive research to explore therapies against these diseases but flawless therapy requires a more extensive effort and we need to focus on several aspects of the disease. Various factors are associated with these diseases. Neurodegenerative diseases are multifactorial showing the interplay of genetic and environmental factors. Among environmental factors, toxic metals, pesticides, particulate matter, smoke and other factors have a role in the risk of these diseases. DNA sequence variations in several human genes are associated with the risk of neurodegenerative diseases. A study of genetic and environmental factors could be helpful for the identification of the risk of an individual human being to a particular neurodegenerative disease. Understanding the mechanism of disease initiation and progression would be vital in the exploration of the therapeutic targets to prevent disease or modify its course.

CONSENT FOR PUBLICATION

Not applicable

CONFLICT OF INTEREST

The author declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

Colligation of Mitochondria Dysfunction and Neurodegeneration: Parkinson’s Disease

K Amrutha¹, Neelam Yadav², Sarika Singh¹, *

¹ Department of Neuroscience and Ageing Biology and Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow – 226031, India

² Department of Biochemistry, RML University, Faizabad, UP, India

Abstract;

Parkinson’s disease (PD) is a first most common motor neurodegenerative disorder and caused due to degeneration of dopaminergic neurons of nigrostriatal pathway of brain. Brain is the most active organ of human body which receives, process and command the responses utilizing approximately twenty percent of body’s total energy. Mitochondrion is the cellular powerhouse produces ATP by utilizing various complexes of electron transport chain. This ATP is the energy source of cells and is being used for physiological functions of the cells, indicating the critical role of mitochondrial functionality in cellular physiology. In PD pathology the impaired bioenergetics is the known and critical factor which essentially requires for cellular physiological responses and failed to maintain it will lead to self-destruction of cell, termed as apoptosis. Neuronal apoptosis is the inescapable event in PD pathology and suggest the implications of cellular bioenergetics and the close conjunction of mitochondrion functionality and disease pathology. In this chapter mitochondrion functionality and its correlation with various neurodegenerative signalling pathways during PD pathology will be discussed.

Keywords: Mitochondrial dysfunction, Neurodegeneration, Parkinson’s disease (PD), Pathology.

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* Corresponding author Sarika Singh: Department of Neuroscience and Ageing Biology and Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow – 226031, India; E-mail: sarika_sin [e-mail]

INTRODUCTION

Parkinson's disease (PD) is the most common motor neurodegenerative disease characterized by preferential loss of dopaminergic neurons of the nigrostriatal pathway that leads to the dopamine deficiency in the substantia nigra (SN) and striatum regions of brain. In spite of research of several decades the information regarding disease onset and its pathological markers is limited. Among known pathological marker the presence of Lewy bodies containing α-synuclein, an

intracellular protein, is well accepted in PD pathology [1]. In regard to symptoms, PD pathology exhibit both motor and non-motor symptoms. The classical parkinsonian motor symptoms include bradykinesia, resting tremor, rigidity and postural instability [1]. The non-motor symptoms include sleep disturbances, depression, cognitive deficits, and autonomic &sensory dysfunction which may be psychological effects along with specific effects of disease onset [1]. In spite of the advancing research on the PD pathology, the exact cause and mechanism behind the PD pathogenesis is still mysterious and need further evaluations. To date various etiological reasons have been suggested by the researchers to be implicated at both cellular as well as genetic level in the disease pathology but still lacunae exist. The concept of mitochondrial dysfunction in PD pathology was identified in 1980s with unwanted generation of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) during synthesis of heroin. MPTP itself is not toxic but able to cross the blood brain barrier and in brain processed with enzyme monoamine oxidase B (MAO-B) to form the toxic cation 1-methyl-4-phenylpyridinium (MPP+). MPP+ is toxic to brain cells as it is selectively taken up by dopaminergic cells and inhibits multiple complexes of the respiratory chain [2] therefore, inhibiting the ATP synthesis or mitochondrial functionality. This finding of 1980s is still significant as MPTP is still being utilized to induce the PD pathology in rodents to understand the disease mechanisms [2].

While considering the genetic aspects, PD can be caused by mutations in genes identified by linkage analyses that are inherited in an autosomal recessive or dominant manner. Mutations in the genes encoding α-synuclein and LRRK2 (leucine-rich repeat kinase 2) are responsible for autosomal dominant forms of PD, presumably by a gain-of-function mechanism. Other mutation implies to loss-of-function which involve mutations in the genes encoding Parkin, PINK1, and DJ-1, which cause functional impairment of mitochondrion and mediates the autosomal recessive PD [1]. Such PD associated functional impairment of mitochondrion caused significant progressive damage to neurons involving various signaling mechanisms mostly involving the ATP driven mechanisms. The major mechanisms which have been investigated in disease pathology are oxidative stress, protein aggregation and degradation mechanisms, compromised protein synthesis and trafficking, alterations in mitochondrial dynamics, affected calcium homeostasis, defective autophagy, DNA damage and initiation of cellular death pathways. In the following section we are focusing on mitochondrial functionality in PD pathology and its correlation with other neurodegenerative signaling pathways during disease pathology.

ROLE OF MITOCHONDRIA IN PD PATHOLOGY

Mitochondria are double membrane bound organelles found in most of the cells of eukaryotic origin. These are the key organelles that produce most of the cellular energy required for the proper functioning of the cell, also known as the power house of the cell. The energy production in mitochondria mainly occurs through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). The electron carriers that generated in TCA cycle contribute their electrons to the electron transport chain (ETC). The OXPHOS consists of four distinct multisubunit complexes (I-IV) and two electron carriers that generate a proton gradient across the mitochondrial inner membrane, which in turn drives ATP synthase (complex V) to generate ATP. The production of ATP is based on the movement of electrons between the complexes and the transport of the protons from matrix to intermembrane space which generate a proton concentration gradient used by the ATP synthase for ATP production. Complex I and III are the centres that give rise to the reactive oxygen species (ROS) including oxygen radicals and hydrogen peroxides during ATP generation. Both complex I and III of ETC can be leaky and leaked electrons may react with the oxygen present in the mitochondrial matrix to form superoxides. Under physiological conditions these free radicals which generate as side products during ATP synthesis, can be abandoned by the available cellular antioxidants however, during pathological conditions the antioxidants level gets depleted thus these free radicals could not be abandoned and may initiate the pathological signalling mechanisms. In neurons, the glycolytic pathway is limited and the energy production is mainly dependent on mitochondria. These mitochondria are mainly present at the synapse, where the energy demand is quite high. It can be move from a presynaptic region to the postsynaptic region of a neuron according to cellular demand of ATP which further reveals the inevitable role of mitochondria in energy biogenesis in neurons. Physiologically mitochondrion that produces ATP actively, lowers the proton motive force, NADH/NAD+ ratio and ROS production. Conversely the ROS production at complex I is increased by the low ATP production due to impaired respiratory chain. The reduction in the ATP production is an expected complication of defective mitochondrial respiration. This has been proved in MPTP induced experimental models of PD that ATP synthesis gets depleted by twenty percent in brain and also in synaptosomal & hepatocyte preparations [3]. Simultaneously, in other article it has been argued that depletion of more than fifty percent of complex I activity cause a significant reduction of ATP production in nonsynaptic brain mitochondria. In PD patients approximately twenty to thirty percent reduction in complex I activity has reported which caused significant ATP depletion and consequent impairment of neuronal physiology [3]. However, another report showed that mutation (A53T mutation) in α-synuclein in rodents also exhibit the mitochondrial dysfunction suggesting the disease specific functional impairment of mitochondrion. Such impaired mitochondrial functions may be due to increased mitochondrial fission, distortion of complex I activity and an increased mitophagy of damaged as well as healthy mitochondria [4] therefore suggesting that such unregulated mitophagy in neurons lead to neuronal cell death due to the decreased mitochondrial number thus depleted ATP level. One report has also suggested that MPP+, a neurotoxin, taken up by dopaminergic neurons caused the inhibition of mitochondrial complex-I activity and induce the PD like