Advances in Diagnostics and Immunotherapeutics for Neurodegenerative Diseases E-Book
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- Herausgeber: Bentham Science Publishers
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- Sprache: Englisch
Advances in Diagnostics and Immunotherapeutics for Neurodegenerative Diseases delves into the intricate mechanisms underlying neurodegenerative disorders and highlights cutting-edge diagnostic methods and innovative immunotherapeutic strategies. This comprehensive book addresses several key themes crucial to understanding and combating these debilitating conditions with an updated understanding of neurodegenerative disorders and a review of the latest advancements in diagnostic and treatment strategies.
Key Themes
Neuroinflammation: examines the complex molecular pathways involved in neuroinflammatory responses and their impact on disease dynamics.
Gut-Brain Axis: A thorough discussion on the relationship between the gut microbiome and neurodegenerative processes is presented.
Advanced Diagnostics: A state-of-the-art review of diagnostic techniques provides updates on advanced neuroimaging modalities, cerebrospinal fluid biomarker analysis, and genetic testing.
Epigenetic Regulation of Microglia: Covers the emerging field of epigenetic modifications and their role in modulating microglial activation and function.
Immunotherapeutics: Learn about the potential of monoclonal antibodies, immune modulators, and repurposed drug therapies in slowing disease progression and improving patient outcomes.
This book serves as a valuable resource for researchers, clinicians, and students in the fields of molecular biology, neuroimmunology, and clinical neurology.
Readership
Researchers, clinicians, and students in the fields of molecular biology, neuroimmunology, and clinical neurology.
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Veröffentlichungsjahr: 2024
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FOREWORD
Neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, are debilitating disorders that affect millions of people worldwide. These conditions are characterized by the progressive loss of function and death of neurons, resulting in a wide range of symptoms, including memory loss, motor impairment, and cognitive decline. Despite extensive research, there is currently no cure for most neurodegenerative conditions, and existing treatments only offer limited symptom relief.
However, there is a ray of hope. In recent years, significant advances have been made in the field of neurodegenerative research, particularly in the areas of diagnostics and immunotherapy. These advances have led to the development of novel diagnostic tools that allow for earlier and more accurate diagnosis of these conditions, as well as promising immunotherapeutic approaches that target the underlying pathologies of these diseases.
This book, Advances in Diagnostic and Immunotherapeutic Approaches for Neurodegenerative Conditions, provides a comprehensive overview of these recent advances, highlighting the most promising developments and providing insights into future directions for research and treatment.
The book focuses on advances in diagnostics, covering topics such as biomarkers for early detection, imaging techniques for improved diagnosis, and the role of genetics in neurodegenerative conditions. The authors explore the potential of these diagnostic tools to enhance early detection and diagnosis, which is crucial for the development of effective treatments, and immunotherapeutic approaches, including novel strategies for targeting misfolded proteins and inflammatory pathways, as well as the use of stem cells and gene therapy. The authors explore the potential of these approaches to slow or even reverse the progression of neurodegenerative conditions, offering hope for the development of effective disease-modifying treatments.
The final section of the book examines the challenges and opportunities presented by these recent advances, exploring topics such as ethical considerations in the development and implementation of these approaches, the potential impact on healthcare systems, and the need for collaboration between researchers, clinicians, and patients.
This book is an essential resource for researchers, clinicians, and students in the fields of neurology, neuroscience, and immunology, as well as for anyone interested in the latest developments in the diagnosis and treatment of neurodegenerative conditions.
Overall, the book “Advances in Diagnostic and Immunotherapeutic Approaches for Neurodegenerative Conditions” represents an important contribution to the field of neurodegenerative research, offering a roadmap for the development of more effective diagnostic and therapeutic approaches, and providing hope for a brighter future for those living with these conditions.
PREFACE
In the intricate landscape of neuroscience, the journey to understanding and combating neurodegenerative conditions has been both challenging and inspiring. "Advances in Diagnostic and Immunotherapeutic Approaches for Neurodegenerative Conditions" endeavors to capture the remarkable strides made in recent years, offering readers a panoramic view of the cutting-edge research shaping the future of neurodegenerative disease management.
Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a complex and multifaceted challenge. These conditions not only affect the individuals diagnosed but also reverberate through families, communities, and healthcare systems worldwide. With the aging population on the rise, the imperative to develop effective diagnostic tools and therapeutic strategies has never been more pressing.
This comprehensive book aims to provide readers with a panoramic view of the latest advancements in diagnostic methodologies, from cutting-edge imaging technologies and biomarker identification to sophisticated genetic profiling techniques. By illuminating these breakthroughs, we strive to enhance our understanding of disease mechanisms, enabling earlier detection, more accurate diagnosis, and personalized treatment approaches.
The latter sections of the book are dedicated to exploring the burgeoning field of immunotherapeutic interventions. Here, we delve into the exciting potential of harnessing the body's immune system to target and combat neurodegenerative processes. The latter chapters in this section showcase the transformative power of immunotherapy in reshaping our approach to treating neurodegenerative conditions.
However, this volume is not merely a compilation of scientific achievements; it is a call to action. By highlighting the most promising developments and discussing the challenges that remain, we hope to inspire collaboration and innovation across disciplines. The complex nature of neurodegenerative research necessitates a multidisciplinary approach, where insights from neuroscience, immunology, genetics, and computational biology converge to drive progress.
As you navigate through the pages of "Advances in Diagnostic and Immunotherapeutic Approaches for Neurodegenerative Conditions," you will encounter the dedication, perseverance, and vision of the scientists, clinicians, and researchers who are leading the charge against neurodegeneration. Their pioneering work, presented here in detail, offers a compelling narrative of hope, resilience, and the relentless pursuit of scientific excellence.
We invite you to embark on this enlightening journey with us, as we explore the present landscape and envision a brighter, healthier future for those affected by neurodegenerative conditions.
INTRODUCTION
In this book, various categories of neurodegenerative conditions are discussed, along with their pathological origins, which include genetic and epigenetic factors, and different therapies such as synthetic drugs, biologicals, and repurposed drugs. The book is divided into three segments.
The first segment covers different categories of neurodegenerative conditions (NDC) and their pathological states of origin. It delves into neuroinflammation and its role in causing Alzheimer's disease (AD), Parkinson's disease (PD), Huntington’s disease (HD), and more. Furthermore, it covers how such inflammatory responses can be held responsible for the generation of NDC. Interestingly, it also sheds light on how such inflammatory pathways open the door to impending therapy and next-generation drug development. This segment also covers immunomodulation associated with degenerative Huntington's disease. The second segment focuses on gut microbiota and their impact on the genesis of brain disorders. It discusses the interplay between gut microbiota and neurodegeneration. The third segment discusses epigenetics and its potential role in intervening in neurodegeneration. Finally, the book explores the use of repurposed drugs in treating NDDs.
List of Contributors
A Systematic Review of Neurodegenerative Diseases: Etiology, Clinical Symptoms, Pathogenesis, and Future Developments
Satya Prakash Singh1,*,Deepti Dwivedi2,Rabiya Ahsan3,Ankur Srivastava4,Ajay Kumar Shukla4Abstract
Neurodegenerative diseases (NDDs) are nervous system disorders that impact around 30 million people globally. Loss of brain tissue is a hallmark symptom of NDDs. Amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson's disease, Alzheimer's disease, and Huntington's disease are among the NDDs caused by protein misfolding and inappropriate processing of proteins. In addition, neurodegeneration has also been linked to oxidative stress, mitochondrial malfunction, and/or environmental variables strongly correlated with aging. Significant evidence has been obtained after years of intensive research that shows these factors have a crucial role in the etiology of prevalent neurodegenerative disorders. Many clues have been identified regarding neurodegenerative illnesses, but the complexities of these conditions still make them difficult to understand. This chapter presents a more straightforward explanation to help individuals better understand NDDs, their etiology, clinical symptoms, and pathogenesis
INTRODUCTION
There is an immediate danger to human health from neurodegenerative illnesses. The ageing of the population has led to an increase in cases of neurodegenerative illnesses such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral
sclerosis (ALS), frontotemporal dementia, and spinocerebellar ataxias. The pathophysiology of these conditions is quite diverse; some of them manifest in memory and cognitive decline, while others manifest in difficulties with locomotion, speech, and respiration [1, 2]. Just to name a few, there are (a) Aberrant protein dynamics with faulty protein aggregation and degradation, (b) Oxidative stress and the formation of free radicals, (c) Poor bioenergetics and dysfunctional mitochondria, and (d) Exposure to pesticides and metal toxicity (Fig. 1). In addition, despite extensive research efforts, the pathophysiology of these proteinopathies remains unclear, making it difficult to identify effective therapeutic drug targets. However, neuroscientists have capitalized on their comprehension of the primary etiology of these disorders to study applications with the aim of producing recently developed new therapeutics for these diseases. Even though every disease has a unique molecular mechanism and set of clinical symptoms, certain common pathways may be identified in various pathogenic cascades. These include oxidative stress and free radical production, metal dyshomeostasis, mitochondrial dysfunction, protein misfolding and aggregation, and phosphorylation impairment, all occurring concurrently.
Fig. (1)) Different factors responsible for the precipitation of neurodegenerative disorders [7].With remarkable progress in genome sequencing technology, we can now read individual genomes and get insight into the origins of both common and unusual genetic illnesses, although Deoxyribonucleic acid (DNA) sequence variants are common, it is not yet known which ones are harmful and only cause a slight change in gene function [3]. Human genome sequencing has led to the identification of candidate gene variants, the effects of which may be evaluated using model animals. A cure for spinal muscular atrophy (SMA) is an inspiring example of scientific advancement. Mutations causing loss of function in the survival motor neuron (SMN1) gene result in SMA, the most common inherited cause of infant mortality. On the heels of ground-breaking research into the molecular basis of the disease and the development of animal models, antisense oligonucleotides (ASOs) are currently being tested in human trials as a therapy option to correct a splicing error and restore functional SMN protein. Researchers verified the promising findings in animal model systems in two clinical trials, including children with SMA. After the approval by the Food Drug Administration (FDA) of the ASO medication at the year's end, it became the first disease-modifying therapy for SMA and a comparison was made between infants who did not receive the medication with those who showed significant gains in motor ability. This is a big win for patients, their loved ones, and the model systems [4].
The healing path forward in the fight against neurodegenerative diseases is now clear. Scientists studying this field are fortunate to be doing their work during such an intriguing and productive time [5, 6]. The primary target of neurodegeneration, which has a multifactorial aetiology, is the neurons in the human brain. This disorder is linked to the gradual loss of brain tissues, which results in the death of neurons. It is directly related to ageing, and one of its primary characteristics is the degeneration of proteins, which leads to the buildup of inclusion bodies and insoluble deposits in different parts of the brain. Neurotoxic oligomers, oxidative stress, neuroinflammation, mitochondrial dysfunction, calcium dysregulation, deficiencies in axonal transport, metal buildup, amyloid deposition, and DNA damage are only a few other factors that have been associated with neurodegeneration (Fig. 1). Through a variety of pathways, including apoptosis, necrosis, autophagy, and parthanatos, programmed cell death eventually results from the persistence of these conditions overwhelming self-defense mechanisms.
Parkinson’s Disease
Neurodegenerative diseases include Parkinson's. When substantia nigra neurons die, movement issues occur. The substantia nigra contains many neurons that produce dopamine. Substantia nigra neurons release dopamine to connect with movement-producing brain regions like the frontal lobe and basal ganglia. Ganglia are neuron clusters. Basal ganglia are neuronal groupings in the brain's core. Neuronal loss in the substantia nigra causes stumbling and trembling in persons with this condition. They have trouble initiating and maintaining movement [7].
Huntington’s Disease
Degenerative brain diseases like Huntington's disease are genetically transferred from parents, which comprise neuropsychiatric changes and involuntary movements. In this cognitive disorder, females and males are affected equally [8, 9]. Symptoms appear at approximately 40 years of age; rare juvenile forms begin in adolescence or childhood [10, 11]. The progression of HD disease depends upon functional and structural changes in the brain, which may be present more than decades before signs and symptoms manifest. Pathology of HD in the earlier phase is striatum and neuro-imaging measures of striatal changes are correlated with neurological and cognitive markers [12, 13]. Neurons dying in neurodegenerative diseases shrink the brain. This creates memory and cognitive issues.
Alzheimer’s Disorders
The most prevalent cause of dementia worldwide is Alzheimer's disease, which places a significant strain on healthcare systems [14]. The earliest records of Alzheimer's disease, dating back to 1907, detailed the specific alterations in cortical cell clusters found in brain biopsies and linked these lesions to the patient's anomalies and behavioural changes. AD is a multifaceted, multifactorial neurodegenerative illness that involves the interplay of an individual's age, education, environment, and genetic composition [15-17]. The amyloid cascade hypothesis, which links the pronounced amyloid-beta peptide presence to clinical signs and symptoms and enhanced deposition into amyloid plaques that eventually lead to nerve cell damage, is currently the most widely accepted theory for the development of Alzheimer's disease [18, 19]. Suppose AD reaches the ancient phase then separately gradually leads to dead memory, also known as memory centred cognitive decline phase. Clinically AD diagnoses by imaging such as positron emission tomography (PET) and amyloid PET, biomarkers in cerebrospinal fluid (CSF), are useful for evaluating patients [20, 21]. AD histology consists initially of extracellular amyloid plaques comprising abnormal Ab peptides and intracellular neurofibrillary tangles, which consist of hyperphosphorylated tau protein. Lastly, these cause gross anatomical findings of atrophy diffusely. Currently, pharmaceutical treatments are available for Alzheimer’s such as memantine and cholinesterase inhibitors. Other goals include improving cognitive reserve and offering a dietary strategy to halt or stop the spread of illnesses [22-26].
Amyotrophic Lateral Sclerosis (ALS)
ALS, sometimes referred to as Lou Gehrig’s disease or, motor neuron disease is a neurological condition that affects motor neurons, the brain, and the spinal cord's nerve cells that regulate voluntary muscle movement and breathing. This can cause paralysis and muscle weakness [27, 28]. Motor neurons in ALS gradually decline until they eventually die [29]. Signals that need to be sent to the brain can no longer be carried when motor neurons are destroyed or injured. More than 70% of ALS cases are caused by changes in four main genes (C9orf72, TARDBP, SOD1, and FUS), despite the fact that over 30 other genes have been associated with the disease [30]. These genes code for a variety of proteins that are involved in major areas of motor function, including homeostasis, mitochondrial function, glial cell function, and DNA repair. It is believed that a combination of these impaired processes plays a role in the motor neuron degeneration observed in ALS. The most prevalent protein seen in most ALS patients is the TAR DNA-binding protein; still, other proteins such as superoxide dismutase-1 and neurofilaments can also form aggregates [31].
Symptoms of Neurodegenerative Diseases
Movement DisordersThe movement disorders can include issues with both voluntary and involuntary movement, like: Chorea, an involuntary jerking or writhing movement, Muscle issues, including dystonia or tightness in the muscles, sluggish or peculiar eye motions, compromised posture, balance, and gait difficulty swallowing or speaking. More impairments to voluntary motions than involuntary ones could affect a person's capacity for employment, day-to-day tasks, communication, and independence.
Memory LossAnyone can suffer from memory loss, and the likelihood of doing so increases with age. However, a neurodegenerative condition like Alzheimer's disease can cause memory loss that is extremely harmful to one's health. Neurodegenerative diseases can damage a person's memory as well as their ability to reason, communicate, and perform daily cognitive tasks. Such disorders cause rapid confusion and disorientation in their sufferers. Disturbances in thinking abilities, language, and judgment are some additional signs. Memory-related disorders associated with these diseases are numerous [32].
ApathyApathy is defined as a person's known lack of interest in social interactions and activities in life as a result of a degenerative illness. Persons having apathy are characterized by a decline in motivation, altered emotional states and behavioral thinking, a negative impact on quality of life, and ongoing behavioral changes. One of the most prevalent signs of neurodegenerative illness is apathy, which can be extremely upsetting for the affected individual [33].
AnxietyThe body's natural reaction to stress and depression is anxiety. When dealing with a degenerative disease, anxiety can be extremely disruptive to daily life and activities. Though anxiety is usually a passing experience, in extreme circumstances, it can interfere with day-to-day functioning and worsen over time. Anxiety-stricken individuals may have raised heart rate, fast breathing, agitation, trouble falling asleep, and difficulties focusing.
Changes in MoodSad mood seems to be present in all major depressive disorders, apparently. Individuals with neurodegenerative diseases may be prone to persistent mood fluctuations and exhibit disinterest in activities related to social, emotional, spiritual, and physical domains. It affects a person’s general well-being. Those who suffer from mood disorders frequently encounter the following symptoms: feeling down most of the time; experiencing a drop in energy; feeling hopeless; losing appetite; gaining weight; sleeping a lot; or having frequent thoughts of suicide or death.
DelusionsMisinterpretations foster delusions. Paranoia is common. Delusional people may believe the government controls our every move via radio waves without evidence.
DisorientationDisorientation is being confused about time, location, or identity. Diseases, medications, infections, and other factors can cause it. Disoriented people may have trouble focusing.
Neurodegenerative syndromes cause permanent injury to the nervous system. Symptoms have a tendency to get worsen as the disease progresses, and new indications are also likely to grow over time [32, 33].
Neurodegeneration: Etiologies
Neurodegeneration is the root cause of disorders like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Neurodegeneration has several causes, including age, genetics, and the environment. Genes and environment both have a role. AD and PD can be family (monogenic and complicated) or sporadic, while HD is genetic. Oxidative stress, proteasomal impairment, and Neurodegenerative disorders are characterised by mitochondrial dysfunction and abnormal protein aggregation. Advances in aetiology and therapy have resulted from a better grasp of the biochemical and molecular processes driving degeneration in human post-mortem brain tissues and animal models [33].
Fig. (2)) Initiation–progression hypothesis of neurodegenerative diseases showing different processes like, (a)Neurodegeneration, (b) Proteinopathies, (c) Neuroinflammation, (d) Neurodegeneration-induced neuroinflammation, (e) Initiation Factors.The pathogenesis and advancement of neurodegeneration are inextricably connected to abnormal protein deposits seen in tauopathies, -synucleinopathies, amyloidosis, and transactivation response DNA binding protein (TDP-43) proteinopathies, which improve motor, sensory, and/or autonomic dysfunctions that are physically equivalent. The molecular changes cause pro-inflammatory cytokines to be released along with the initiation of microglia and astrocytes. This increases the generation of highly reactive oxygen and nitrogen species (ROS and RNS), which in turn injure surrounding tissues and activate nearby glial cells. The majority of affected areas are cognitive, and psychobehavioral indicators like anxiety and sadness are common among NDs (Fig. 2) [33]. The primary histopathologic features necessary for determining a specific neuropathologic diagnosis are aberrant protein conformations in these illnesses, together with their cellular and neuroanatomical distribution.
Tau in neurofibrillary tangles (NFTs) or Pick bodies, -synuclein in Lewy bodies, and TDP-43 in neuronal cytoplasmic and neuronal intranuclear inclusions are a few examples of protein accumulations within neurons. Tau is accumulated in tufted astrocytes, astrocytic plaques, and thorn-shaped astrocytes inside astrocytes. The oligodendroglia accumulates proteins such as tau in coiled bodies and -synuclein in glial cytoplasmic inclusions. In contrast to the neuronal presence found in viral infections, where the protein is external, these aberrant protein aggregates are made up of cellular components and proteins that are naturally present in neurons. The protein frequently has an aberrant structure with amyloid-like characteristics. The majority of these aggregates take the shape of filaments, in addition to their secondary structures rich in sheets that are pleated. Protein accumulations within neurons include a variety of aggregates, such as amyloid plaques, NFTs, and a subset of Lewy bodies, which can be seen using amyloid stains like Congo red, and thioflavin S. Silver-staining techniques, however, are more effective in identifying other aggregates. Due to its higher interlaboratory and interrater dependability, immunohistochemistry is currently the method of choice for researching neurodegenerative diseases [34]. Although HD is autosomal, creating a mouse model that accurately represents all of the disease's clinical and pathological appearances has been challenging. The brains of transgenic HD rats show histological changes, as mentioned. It discusses the possible role of glial cells and the use of transgenic mice in diagnosis and therapy. The progression of neurodegenerative disorders must be delayed or stopped entirely. Natural agents may be safer than artificial ones. Oxidative stress and behavioral deficits generated by amyloid-peptide are mitigated by a Borago officinalis extract. They show that the extracts of Borago officinalis enhance memory. It is essential for any drug with an active or pro ingredient to be able to cross the blood-brain barrier [35]. In vivo microdialysis is used to differentiate between normal and 6-hydroxydopamine-induced parkinsonism (N-[2-(4-hydroxyphenyl)-ethyl] -2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4- 22hydroxy-phenyl)-acrylamide. The results might pave the way for human testing of bioactive molecules. Neurodegenerative disease is notoriously difficult to diagnose and differentiate. In vivo, optical imaging is emphasised by Patterson et al. for the study of neurodegeneration. The authors stress the importance of imaging methods, in the diagnosis and monitoring of neurodegenerative illnesses, in addition to fluorescent and bioluminescent compounds. It is not clear whether inflammation has a function in neurodegeneration. Inflammatory variables and the immune system are investigated as possible therapeutic targets to control the immunological response, which plays a role in the genesis of PD. The role of microglia in ischemic stroke and treatment strategies to alter microglial response were recently emphasised [36]. It might be challenging to draw a direct line between the signs of neurodegenerative diseases and their underlying causes in the clinic. The most effective method of transporting pharmacological medications to the brain is the monitoring and assessment of novel therapy, and identification of possible molecular targets, which will require extensive research. It will inspire researchers to focus on these problems in pursuing a cure for a widespread array of neurological illnesses that now have no effective treatment [37].
Ageing: Relevant to the Growth of Neurodegenerative Disorders
Ageing is the steady decline of biological processes after an organism reaches its reproductive peak. Ageing causes limitations and disorders that impede normal body functions and increase neurological disease risk [38]. Neurodegenerative disorders end with oxidative and nitrative stress. According to the free radical hypothesis of ageing, ROS and RNS damage neuronal membranes and cause oxidative and nitrative stress. Even without neurodegenerative disorders, oxidative and nitrative stress cause cognitive and motor impairment in the aged. Neurodegenerative diseases are produced by oxidative and nitrative stress. Chronic neurodegenerative ailments are affected by diet. Positive effects on signal transduction, gene expression, and brain communication have been shown after treatment with polyphenols, resveratrol, ginkgo Biloba, curcumin, ferulic acid, carotenoids, flavonoids, and n-3 fatty acids. Aging increases the risk of developing neurodegenerative diseases. No one hypothesis of ageing explains all ageing changes. Ageing is a complex, inevitable process. Humans may be more susceptible to illness in old age due to declining physiological processes and oxidative stress tolerance. New information about ageing has proliferated. Vintages and specific genes may control ageing and lifespan, according to research. Researchers should investigate ways to increase human longevity and to age actively and disease-free (healthy longevity) [39]. Neurodegenerative disorders involve varied processes associated with many pathogens. Unbalanced Reactive Oxygen Species (ROS) and Repetitive nerve stimulation (RNS) production can cause oxidative and nitrative stressors, which can cause neuronal injury and apoptosis or necrosis. Multiple genetic abnormalities and vulnerability to epigenetic or environmental variables cause these disorders. Understanding the pharmacogenomics of neurodegenerative illnesses may speed up the development of more effective and safer anti-ageing medications [40].
Neurodegenerative Disorders Caused by Mitochondrial Dysfunction
Diabetes, cardiomyopathy, and a progressive inability to walk or use arms and legs characterise those who suffer from Friedreich's ataxia. It occurs once every 50,000 people. Lowered frataxin levels are due to transcriptional interference caused by an extension of the acid alpha-glucosidase (GAA) trinucleotide repeat in the primary intron of a chromosome [41] gene. Degeneration happens most rapidly in the heart, spinal cord, and dorsal root ganglia, all of which have the highest transcription levels of frataxin. The yeast homolog of frataxin illuminates the pathogenesis of diseases. Breathing problems, an inability to do oxidative phosphorylation, the loss of mitochondrial DNA, an overload of iron, and heightened vulnerability to hydrogen peroxide-mediated oxidative stress are all the results of disrupting genes in yeast. The damage to mitochondria from an iron overload is dose and duration-dependent [4].
Human frataxin is associated with mitochondrial membranes. Friedreich's ataxia causes enzymes like aconitase, which include iron-sulfur clusters, to be less active [35]. Friedreich's ataxia patients have more iron in their dentate nucleus and fibroblasts, and their fibroblasts are more sensitive to H2O2. In vivo ATP synthesis is hindered in Friedreich's ataxia muscle, related to the high number of GAA, which repeats in the frataxin gene. Urine 8-hydroxy-2-deoxyguanosine levels above normal may indicate oxidative stress. Friedreich's ataxia-like symptoms are caused by alterations in the protein that binds vitamin E. The role of mitochondrial dysfunction and oxidative damage in disease aetiology is supported by the data [5].
Recent Treatments of Cognitive Impairments
Recent medications for Creutzfeldt -Jakob disease, Huntington's disease, epilepsy, Alzheimer’s disorders, Parkinson's disease, and schizophrenia are shown in Table 1. All medications are approved by Food Drug Administration.
Pathologies that Mitochondrial DNA Mutations may Cause
Some cases of spontaneous ALS have been linked to mitochondrial dysfunction and Sporadic amyotrophic lateral sclerosis (SALS). Both mitochondrial abnormalities in SALS samples and anterior horn cells were found. Mitochondrial biopsies taken from SALS patients show a 50% decrease in complex activity compared to age-matched controls [46]. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and flavoprotein autofluorescence areresponsible for functional imaging of mitochondria in permeabilized muscle fibres, which reveal abnormalities at the level of a single thread. More mitochondria and calcium can be seen in SALS biopsies. The cytochrome-oxidase activity of motoneurons in SALS patients was reduced. These individuals' peripheral blood cells show increased cytosolic Ca and inadequate responses to oxidative phosphorylation uncouplers. Recent studies of ALS cybrids have shown that complex-I activity is decreased, complex-III and complex-IV activity are reduced, and free-radical-scavenging enzymes are increased [47]. These patients have an out-of-frame mutation in the cytochrome oxidase subunit and one gene of mitochondrial DNA, thereby causing motor neuron disease. There is growing evidence that SALS is influenced by mitochondrial malfunction and oxidative stress. Copper-zinc superoxide dismutase (SOD1) abnormalities are linked to hereditary ALS that has an autosomal dominant inheritance pattern (SOD1). The mitochondrial membrane potential drops, and cytosolic Ca68 rises due to the G93A Sod1 mutation. Mice engineered to develop ALS by mutating Sod1 have revealed that vacuolization of mitochondria is a harmful feature that precedes motor impairment and motoneurons [48]. The mitochondrial malfunction has been connected to SALS and familial ALS caused by Sod1 mutations. Neurodegeneration disease is related to mitochondrial dysfunction, oxidative damage, or both, according to studies of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) [49]. Toxins like MPTP were first identified as a contaminant in synthetic opiates, where they manifest as Parkinsonism in young individuals. To decrease ATP production, MPTP is metabolised into MPP1 (1-methyl-4-phenylpyridinium). Staining for complex-I subunits is reduced by 30-40% in the substantial nigra of patients with idiopathic Parkinson's disease (PD) but staining for other electron-transport subunits is preserved. Two studies show that PD cybrids have lower complex-I activity, suggesting that this impairment is encoded in the mitochondrial DNA. These variations amplify mitochondrial Ca21 buffering, free-radical production, and MPTP metabolite susceptibility [2]. A complex-I mutation causes Parkinsonism in a person with multisystem atrophy. We infer that complex-I deficiency results from heteroblastic mutations or genetic/environmental interactions since direct sequencing of mtDNA complex-I and tRNA genes failed to demonstrate homoplastic alterations [50, 51].
CONCLUSION AND FUTURE DEVELOPMENTS
Nearly all NDD has been unraveled on the genetic basis in the previous two decades. Given their shared phenotypes and pathologies, their illness genes should disclose new neuronal health pathways. Mitochondrial bioenergetics, lipid metabolism, and autophagy/mitophagy are all suggested as Neurodegeneration with Brain Iron Accumulation (NBIA) activities due to their involvement in intersecting paths. Moreover, defects in these pathways harm basal ganglia cells and cause iron imbalances. Despite genetic breakthroughs, there are no curative ordisease-modifying NBIA medicines. For several NBIA diseases, there are some appropriate therapies. These include small-molecule substitution and gene transfer. Although their therapeutic effectiveness is questionable. Effective treatments will encourage the development of early diagnostic technologies and disease biomarkers. Genetics has significantly impacted NBIA. Disease gene discovery underpins NBIA disease biology. New gene discoveries speed up others. Gene transfer and other gene-based therapies are promising for NBIA illnesses, and early genetic screening will determine who may benefit. Genetics will continue to affect NBIA for many years, notwithstanding the end of gene discovery with respect to the disease.
