Neurodegenerative Diseases: Multifactorial Degenerative Processes, Biomarkers and Therapeutic Approaches E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
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.
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Seitenzahl: 534
Veröffentlichungsjahr: 2002
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PREFACE
There are fourteen chapters in this book entitled " Neurodegenerative Diseases: Multifactorial Degenerative Processes, Biomarkers and Therapeutic Approaches." The book focuses on the current trends in pathophysiology, biomarkers, and therapeutic approaches for neurodegenerative diseases.
The goal of this book is to give readers an overview of multiple degenerative mechanisms in neurodegeneration, as well as biomarkers and therapeutic possibilities. The book is aimed to target students, research scholars, and neuro physicians who are interested in the topic. The book's structure is well-organized and updated.
This book is divided into three sections, each of which covers a different facet of the disease. Part I, which contains four chapters, is about multifactorial degenerative processes in neurodegenerative diseases; chapter 1 by Tabish Qidwai discusses multifactorial degeneration and the role of genetic and environmental factors in neurodegenerative diseases.
Sarika Singh et al. in chapter 2 outline the role of mitochondrial dysfunction. Chapter 3 by Mishra et al. presents the role of protein aggregation in neurodegenerative diseases. In chapter 4, Prakash et al., describe the reactive oxygen species in neurodegenerative diseases.
Part-II is focussed on pathophysiology, and biomarkers in neurodegenerative diseases. This part consists of six chapters; molecular biology, pathophysiology, and biomarkers of Parkinson's disease are discussed in chapter 5 by Arshad et al. In the chapter 6, Yadav et al., discuss the molecular basis, pathophysiology and biomarkers of Alzheimer's disease. Chapter 7 by Siddiqui reviews the molecular basis, pathophysiology and biomarker of Huntington's disease. Prakash et al., in chapter 8, describes the molecular biology, pathophysiology and biomarkers of multiple sclerosis. Chapter 9, by Subhadip Chakraborty, discusses the molecular diagnostics and immunological markers of neurodegenerative diseases. In chapter 10, Dinesh Yadav describes the omics approaches for biomarkers investigation in neurodegenerative diseases.
Part-III of the book covers the therapeutic approaches for neurodegenerative diseases, this part consists of four chapters; In Chapter 11, Rajesh Ugale focuses on emerging therapeutic approaches for neurodegenerative diseases. Chapter 12 by Singh et al., reviews the role of medicinal plants and natural compounds as antiparkinson agents. In chapter 13, Bandana outlines the neuropharmacology apporach in Alzheimer's and Huntington's disease. The last chapter by Vandana et al., describes the description of public health and the burden of neurodegenerative diseases.
This book, I believe, will be of tremendous interest to students, doctors, researchers, and even patients and their families. Finally, I would like to express my gratitude to all of the contributors to this book, as well as the Bentham Publishing Editorial Board for providing us with this invaluable opportunity.
List of Contributors
Neurodegenerative Diseases Involve Multifactorial Interplay of Genetics and Environmental Factors
Tabish Qidwai1,*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.
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.
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K Amrutha1,Neelam Yadav2,Sarika Singh1,*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.
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 symptoms and pathology [2] further reflects the implication of mitochondrial physiology in PD pathology. Later on in post mortem brain of PD patients also the similar reduction in mitochondrial complex-I activity was reported [2]. In line now-a-days various inhibitors of mitochondrial complexes like MPTP, paraquat and rotenone are being used in research to induce the PD pathology in rodents to study the disease mechanism [2]. In spite of various report to date it is only known that mitochondrial complex I impairment is one of the cause of PD pathology but its specific cause is not yet known. Few reports have suggested the role of nuclear and mitochondrial DNA mutations but further explorations are required.
MITOCHONDRIAL MUTATIONS IN PD PATHOLOGY
Mitochondria contains different proteins including genes encoded by the nuclear DNA while the respiratory complex proteins are encoded by the mitochondrial DNA (mtDNA). The mtDNA is more vulnerable to the mutations than nuclear DNA. The point mutations, deletions or alterations in mtDNA copy number are the different mtDNA modifications that occur and also increase with aging and during pathological conditions. Mutations in mtDNA polymerase gamma 1 (POLG1), mitochondrial transcription factor A (TFAM), DNA helicase Twinkle (TWNK), and the single-stranded binding protein (mtSSB) are the risk factors for PD [5]. MtDNA synthesis, repair and replication is regulated by POLG1 and the mutations in this gene reduce the mtDNA copy number which is evident in few PD patients [5]. Some reports also suggested the point mutations in primary mtDNA in PD pathology. It was reported that the point mutations are evident (m.1555A>C:MT-RNR1) in the 12S rRNA gene [6] and T1095C point mutaion in the same gene (m.1095A>C:MT-RNR1) [7] however, these cases were responsive to levodopa treatment. Another missense mutation in complex-I subunits of mtDNA was also found [8] where reduced complex-I activity is reported in PD patients. Base pairs deletion in mtDNA is also common cause of failure in ATP production due to the partial or complete removal of the mitochondrial protein complexes [9]. This deletion can be one of the cause for the progression of PD. When compared with patients with other neurodegenerative disorders like AD, the mtDNA deletions are more prevalent in PD patients [5]. Once occur such mutation may remain in progeny and may contribute in inheritance of disease. Mutations in mtDNA can also be caused by the ROS generated inside the mitochondria during aging. By using PCR experiments it was identified that respiratory chain defects were seen on age dependent mtDNA deletions in dopaminergic neurons in (substantia nigra pars compacta) SNpc and these deletions are slightly higher in PD patients when compared with the age matched controls [10]. Along with it a study on conditional knock out of TFAM showed the reduced level of mtDNA defects in respiratory chain and neuronal cell death in dopaminergic neurons of midbrain and remain responsive to levodopa therapy indicates a link between mtDNA and neurodegeneration [10]. However, still a clear evidence of mtDNA mutations in PD as the primary cause has not yet proved but observations suggested that these mutations cause defective respiratory chain which leads to the energy depletion and consequent degeneration of neurons.
OTHER MUTATIONS RELATED TO MITOCHONDRIAL FUNCTIONS IN PD PATHOLOGY
In addition to mutation in mtDNA there are few other proteins which are associated with mitochondrial functions and get mutated in PD pathology. In 1997, it was described for the first time that PD can be caused by the variation in the α-synuclein gene (SNCA). Further studies on genetic variations have put forward the influence of different genes in the PD pathology. Particularly, the autosomal dominantly inherited genes SNCA, Leucine-rich repeat kinase 2 (LRRK2), and Vacuolar protein sorting-associated protein 35 (VPS35) and the autosomal recessively transmitted genes Parkin, PINK1, and DJ-1 are identified and validated to cause PD when mutated [1]. In the following section we are providing the details regarding mutation in genes majorly involved in disease pathology.
Parkin
Parkin (Parkinson juvenile disease protein 2) is encoded by PARK2 gene and has enzymatic activity. It is a causative gene for an autosomal recessive form of Parkinson's disease and located on the 6q chromosome. Mutations in this gene are known to cause a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinson's disease (AR-JP) [11]. Under physiological conditions the parkin gene enhances the ubiquitination process, regulate the apoptotic pathway via non degradative ubiquitin signalling and also contribute in regulation of mitophagy and vesicular transport, to maintain mitochondrial homeostasis. The proteasome-mediated degradation of numerous proteins in vitro is involved in parkin gene [12]. Parkin is localized in mitochondria where it binds to mitochondrial transcription factor to regulate mitochondrial transcription and replication. Moreover, parkin overexpression prevented the ceramide-induced mitochondrial swelling and cytochrome c release [12, 13]. The studies also suggested that Parkin knockout mice have reduced mitochondrial complex I and IV activity while in homozygous parkin mutations in humans the impaired mitochondrial complex I and IV activities have observed in leukocytes which proves the pivotal role of parkin gene in mitochondrial homeostasis. Accumulation of toxic protein aggregates due to mutations in parkin gene leads to autosomal-recessive juvenile parkinsonism which primarily indicate a loss of E3 ubiquitin ligase activity of parkin gene [13]. Together with it, parkin mutations can significantly decrease the mitochondrial complex I activity in sporadic PD patients [10].
PINK 1 and DJ-1
PTEN-induced putative kinase 1 (PINK 1) is a serine/threonine kinase located in the inner mitochondrial membrane that protects the neurons from cellular stress. Autosomal recessive form of PD is directly related to PINK1 mutation that diminishes the kinase activity of PINK1 [14]. Several reports suggested the positive role of PINK1 in the regulation of mitochondrial fission that can controls mitochondrial dynamics. The dysregulation of fusion–fission dynamics of mitochondria can contribute to the degeneration of dopaminergic neuron [15, 16]. PINK1 knock down in SH-SY5Y cells had shown an increased mitochondrial oxidative stress, fragmentation and enhanced autophagy [17]. Recent studies pointed out the PINK1-Parkin activity in the elimination of damaged mitochondria [18] suggesting that PD may be aroused due to the accumulation of dysfunctional mitochondria in the neurons [18]. DJ-1 gene is also associated with the autosomal recessive form of PD which is present in the mitochondria and protects the neuronal death due to oxidative stress. An increased mitochondrial oxidative stress, fragmentation and increased autophagy is also identified with the loss of DJ-1in the neurons which correlates the antioxidant role of DJ-1 in the neurons [17].
α-Synuclein
α-synuclein is a small 140 amino acid protein which is encoded by the SNCA gene. It is a key component of Lewy bodies which is the pathological hallmark of Parkinson's disease and found in an aggregated and fibrillar form. It localizes specifically to the nerve terminal and inhibits neurotransmitter release when over-expressed but the knockout has a modest effect on synaptic transmission indicating alternative presynaptic roles. Mutations in α-synuclein (SNCA) are a rare cause of autosomal dominant Parkinson's disease for a small part of familial cases and whole gene multiplications have been discovered to cause the disease together with a few missense mutations. These missense mutations include A53T, A30P and E46K. The two new mutations in PD cases are described as: H50Q and G51D [19, 20]. The mechanism with which these SNCA point mutations initiate the disease cascade remains unknown, in contrast to whole gene multiplications which are likely to cause disease through increased production of α-synuclein. The genetic mutation in α-synuclein causes familial PD and showed their functional relationship to mitochondrial dysfunction [21]. It indicates that α-synuclein can interact with mitochondria by binding to the outer mitochondrial membrane and can be imported under certain conditions as well as interact with the F-type ATPase. This raises the possibility that there is a salient relationship between α-synuclein and mitochondria under physiological and pathological conditions [21]. The studies suggested that the mitochondria of PD patients show accumulation of α-synuclein in substantia nigra and striatum [4].
Leucine-rich Repeat Kinase 2 (LRRK2)
LRRK2 is a large, widely expressed, multi-domain and multifunctional protein. It is classified as a member of the ROCO superfamily and characterized by the presence of tandem Ras of complex (Roc) G-domain, kinase domains and carboxy-terminal of Roc (COR) sequence which links them [22]. The physiological functions of LRRK2 can be demonstrated from its two distinct enzymatic domains: the kinase domain that catalyzes the phosphorylation while the ROC-GTPase domain is involved in GTP-GDP hydrolysis. Mutations in the gene encoding LRRK2 are common genetic risk factors for both familial and sporadic Parkinson’s disease (PD). The most frequent G2019S substitution leads to a gain of function which is associated with increased LRRK2 kinase activity [22]. Several mutations in LRRK2 have been shown to induce changes in its activity and abnormal increase in LRRK2 kinase activity to contribute to PD pathology. Caspase inhibitors blocked the overexpression of LRRK2 mutated proteins in vitro leads to apoptotic neuronal cell death and required Apaf1 indicating that LRRK2 mutations cause mitochondrial dysfunction [23]. Another LRRK2 mutation that is G2019S mutation can also cause defects in mitochondrial morphology and dynamics in the cortical neurons [24]. It has been reported that in PD patients carrying LRRK2 G2019S mutation as a result of mitochondrial dysfunction showed a decrease in mitochondrial membrane potential and low level of total intracellular ATP. Additionally, mitochondrial elongation and interconnectivity were also raised in patients indicating that LRRK2 mutations which affect the mitochondrial function and morphology [25]. LRRK2 was bind to outer mitochondrial membrane, localized in rat mitochondria [26]. Mitochondrial dysfunction has been observed in fibroblasts and iPSC-derived neural cells from PD patients with LRRK2 mutations and has been shown to localize to mitochondria and to regulate its function [22]. It is also involved in the pathogenesis of autosomal recessive PD forms linked to PARK2 and PINK1 encoding the cytosolic E3 ubiquitin-protein ligase, Parkin and the mitochondrial kinase, PINK1. These proteins jointly regulate various mechanisms of mitochondrial quality control including mitophagy.
ROLE OF MITOCHONDRIA IN ENDOPLASMIC RETICULUM STRESS MEDIATED NEURODEGENERATIVE SIGNALLING IN PD PATHOLOGY
Endoplasmic reticulum (ER) is a membrane bound organelle which remains associated with other cellular organelle to accomplish the physiological mechanisms. Among this mitochondrion have a distinguished connection with the ER via mitochondria-associated membrane (MAM). This contact of mitochondria with ER helps them to regulate various cellular functions [27]. Mitochondria are having their own fusion-fission dynamics to tolerate the cellular stress responses and to remove the damaged mitochondria. The studies have already given an indication that mitochondrial fission was commenced from the point of connection of ER to the mitochondria through membrane [27]. Together with these evidences, mitochondrial fusion can also be regulated by the ER contact to the mitochondria. MFN1 and MFN2 are the mitochondrial fusion proteins in which MFN1 has a role in the fusion process while MFN2 is for the stabilisation of the mitochondrial network together with MAM formation [27]. The activity of ER localised MFN2 is regulated by the mitochondrial ubiquitin ligase called MITOL [27
