neurogenerative disorders

neurogenerative disorders

The term neurodegeneration is etymologically derived from two words, which are neuro, which means nerve cells, and other is degeneration, which is the process of losing structure or function. It is commonly used and universally assumed to be understood. Any pathological condition that primarily affects neurons is corresponded by neurodegeneration.Large groups of neurological disorders with heterogeneous clinical and pathological expression affecting specific subsets of neurons in specific functional anatomic systems are practically represented by neurogenerative diseases.

There are hundreds of neurogenerative disorders, but more attention is diverted to the few, which includes the following Alzheimer’s disease, Huntington disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Other forms of neurogenerative disorders have remained less frequent or less publicized hence ignored, although they are devastating.

Increasing age is the significant risk factor for developing neurogenerative disorder more so Parkinson’s disease and Alzheimer’s disease. In industrialized countries, the population aged sixty-five years and above has suffered more, and it is anticipated that the coming generations the rate of infection will grow to the extent of doubling the current price.

The actual cause of the neurogenerative disease remains unknown, and even after identification, the mechanism that initiates the disease remains just mere speculation. Like it’s still uncertain about how the mutant huntingtin provokes Alzheimer’s disease decade later after its identification. The role of genetic and environmental factors that play a part in the initiation of these diseases still remain ferocious debate that surrounds the etiology of neurogenerative disorders. The disease runs as autosomal dominant traits in dentatorubral pallidoluysian atrophy and Huntington disease to the affected family.

Describe proteinopathy

Diseases like Alzheimer’s disease, Parkinson’s disease, Huntington disease, and frontotemporal dementia are neurogenerative disorders, which are proteinopathies and are associated with aggregation and accumulation of misfolded proteins. Several challenges have hindered the translation of preclinical therapies targeting pathways downstream of the initiating proteinopathies hence rendering remarkable progress of understanding the triggers of the condition useless. Little success has been made in clinical trials in symptomatic patients using therapies directed toward initiating the trigger events hence prompting concerns that such therapeutics are of less importance when used in advanced stages of the disease rather than prophylactics.

Several studies have found that neurogenerative diseases are implicated by a critical molecular pathway, which is the misfolding, aggregation, and accumulation of protein in the brain. Accumulation of misfolded proteins has been strongly supported as the leading cause of synaptic dysfunction, neural apoptosis, brain damage, and also disease. It’s still unclear the mechanism by which protein misfolding and aggregations triggers neurodegeneration and the identity of the neurotoxic structure. Clinical manifestation, neurodegenerative disorders share standard features like appearance late in life, the extensive neuronal loss and synaptic abnormalities and presence of cerebral deposits of misfolded proteins aggregates besides their essential differences. The main protein components are different in every disease, but also these deposits are typical disease indicators. Protein components have similar structural, straining, and morphological characteristics. The extracellular protein component found in Alzheimer disease is Amyloid and systematic disorder, but currently, it is referred to as disease-associated protein aggregates

The composition and distribution of proteins totals in each neurogenerative illness are different. In Alzheimer’s, there are two types of protein deposits, which include Amyloid plaques, which are deposited in the extracellular of the brain parenchyma and around cerebral vessels, which constitute 40-42 as the main component of residue peptide termed as Beta-amyloid protein. The neurofibrillary tangles composed of aggregates of hyperphosphorylated tau proteins, which are located on the cytoplasm of degenerating neurons. The fragments of protein a-synuclein are the significant components of these aggregates. Intracellular deposits of a polyglutamine rich version of huntingtin protein are typical features in the brain for patients suffering from Huntington disease. There is an accumulation of protease-resistance aggregates of the prion protein in the minds of humans and animals with transmissible spongiform encephalopathy. Ubiquitinated protein is a result of the accumulation of protein aggregates in a cell is a common cause of many degenerative diseases. Diseases that are likely to be caused by the accumulation of ubiquitinated proteins include Parkinson’s disease.

Biochemical, genetics, and neuropathological studies have come up with compelling evidence that supports the involvement of protein misfolding and aggregation In the neurogenerative disease pathology. The brain region is mostly damaged by the presence of abnormal aggregates as a result of the disease.

Mechanisms to describe proteinopathy.

Neuropathological and neurodegenerative changes precede the presentation of overt neurological symptoms, which are mostly neurogenerative diseases which are characterized by long term prodromal phase. Typically, seventy-five percentage or more of the dopaminergic input to the striatum is always lost before classic motor symptoms arise in Parkinson’s disease. Over the decade, there is progressive loss of this input that reflects dopaminergic cell death in the substantia nigra pars compacta. Dilemma develops when there is a long delay between disease onset and clinical symptoms in developing and testing treatment that target proteinopathy. Symptomatic patients in the current paradigm for clinical developments, novel, and trigger-targeting therapeutics are typically tested. The ability to demonstrate the importance of novel disease-modifying therapies has been limited by the therapeutic development of the paradigm, which has resulted in a shift toward trials in prodromal disease state in Alzheimer’s disease. The initial therapeutic test in symptomatic individuals required in the current road map for developing the disease-modifying therapies for most neurodegenerative diseases.

There are many questions that go unanswered concerning the importance and relevance of the paranoid mechanism in most human CNS proteinopathies besides the emergence of prionoid hypothesis to explain proteinopathy spread within the brain. Responding to these concerns boost awareness of disease progression and also gives an insight into the therapeutic tractability of targeting this pathway. Defining the seed has been one of the major challenges in this field. Precise structural understanding is lacking besides the hypothesized that seed contains structurally altered forms of normal proteins. Theoretically, the seed represents attractive, albeit elusive, and target gave the likelihood that the seed is present in the trace quantity in initial disease.

The process by which cell to cell transmission occurs is still a perplexing question for intracellular proteinopathies. There is growing evidence that these proteins are present at a low level and can also be secreted in cerebrospinal and interstitial fluid if protein implicated in intracellular proteinopathies are hugely localized to the cytoplasm, nucleus or part of scaffolding network of the cell.

The difference between prionoid and prion mechanism is another unknown, but according to their definition prionoids cannot be transmitted but prions can be transmitted. There is no human data to support human to human transmission of any CNS proteinopathy other than prions some experiments have raise the specter that certain proteinopathies can be transmitted from one genetically manipulated mouse to another.

Whether cytoplasmic or organelle-bound intracellular aggregates can act as DAMPs and activate the intracellular immune pathway, it has been considered as an area that has received less attention. Intracellular pathogens resemble both fibrillar and oligomeric assemblies of protein. According to the ALS model, expression of microglia and mutants SODI in an astrocyte plays a major role in disease progression meditation hence implicating some functions of these aggregates inactivation of intrinsic pathways that may contribute to neurotoxicity. Some of the disruptions that affect proteostasis networks are age-related, which have often been invoked to give an explanation as to why many proteinopathies are late-onset diseases and continuous increase in prevalence with age. Identification of any age-related changes within the proteostasis network has become a major challenge. Triplet expansion in Huntington disease, aggressive presently mutation, increased copy of normal synuclein, and various spinocerebellar ataxias are some of the genetic alterations that demonstrate intrinsic factors that self-aggregation of protein that can trump any age and cause disease at an early age.

The failure of the proteostasis network to handle the already altered proteins can be clearly demonstrated by the presence of proteinopathy. Induction of multiple proteinopathies can be as a result of triggering of the protein to aggregate by depleting chaperones required for proteostasis. Various diseases are put in color blocks, which indicates primary proteinaceous aggregate. Alzheimer’s disease designated orange since it has a primary proteinaceous aggregate of both tau, which is in red color and Ab, which is yellow in color. Diseases are colored to be distinguished in at least some cases of the diseases with lines. The diagram below shows a clear picture of mechanisms to describe proteinopathy.

Hypothesis of Neurodegeneration

There is the existence of the harmful network in the brains of neurogenerative disorders, which are Huntington disease, Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, which have been indicated by growing evidence. The intimate interaction among key pathogenic factors that include aberrant calcium homeostasis, metabolic compromise, oxidative damage, and under certain circumstances, amyloid precursor protein mismetabolism forms a very deleterious network. According to the new theory, it states that deleterious network is just a common pathway of degenerating disorders which can be caused by various facts which include the following: genetic factor or environmental factors which leads to a cascade of pathological alteration of the illness or it can be triggered by the age factor. Provision of most appealing hypotheses about neurogenerative diseases and consistent provisional of explanation to a bigger number of observations about these diseases than other hypotheses has been synthesized buy this new theory. Interaction of key detrimental factors is most likely cause of these disorders; hence, it better that patients suffering from neurodegenerative diseases should be treated by combative application of drugs, which can minimize calcium mismetabolism, metabolic compromise, and peroxidative damage.

Molecular pathology of neurodegeneration

Neurons associated with pathologically altered proteins that deposit primarily in the human brain and spinal cord, progressive loss of synapses, and selective dysfunction are the explicit characterization of neurodegenerative diseases. Biochemically detectable proteins and spectrum of distinct immunohistochemically have been identified by recent discoveries to serve as the basis for the classification of protein-based diseases. The procedure of staging a disease has been proposed, and criteria for diagnosing have been updated. The changes are a result of novel concepts that recognize that proteins, in most cases, follow sequential distribution order in the brain hence suggesting the cell to cell propagation and seeding mechanism. Proteins that are associated with neurodegeneration can be detected in peripheral organs. Neurodegenerative associated protein in the presence of concomitant is more of the rule than the exception. The fact that clinical symptoms do not unequivocally indicate molecular pathological background together with these concepts put neuropathological examination at the pivot of the requirements for an accurate diagnosis. Regulations for quality in clinical and neuroimaging, biomarker advancement, the increased demand to better human brain disorder from the general public as well as evaluation of therapy trial indicates the need of renaissance of postmortem neuropathological studies at this era. The recent advances in the neuropathological diagnosis have been summarized in this review and novel report on the relevant aspects for general pathological practices have also been summarized

New findings in proteinopathy

TDP-43, it is abnormalities of RNA binding protein that occurs in Front- Temporal and Amyotrophic Lateral Sclerosis provided the opportunity to design therapies that treat this disease that is currently without effective treatment. The ability to keep certain unwanted coding elements of genes that are known as cryptic is compromised in the brain with FTD as a result of clearing TDP-43 from the nucleus of the nerve cell. The loss of TDP-43 plays a crucial role in causing the nerve cell loss in the affected patients as it is indicated in the discovery. As a result of new findings, a set of experiment has been designed to investigate the actual cause FTD and ALS, monitor abnormalities that occur in the spinal fluid or blood of patients and test a therapy that is designed to slow down nerve cell loss. This type of treatment can be tested in the future to patients with FTD and ALS if it becomes successful.

Inclusion of TDP -43 has been proved that they are not pathognomonic for FTLD-TDP-143 or ALS are also observed in Alzheimer’s disease as a result of the addition.TDP-43 has different cellular functions and is also a heterogeneous nuclear ribonucleoprotein. It helps to bring stability, processing, and translation in mRNA and even negative regulation of alternative splicing.TDP is expressed in many tissues when it is under reasonable condition. These tissues include the nuclei of neurons and glial cells.TDP-43 was previously named FTLD-U, and in the process, there is a loss of nuclear TDP -43, and pathological aggregates in the cytoplasm are formed. Material extracted from the brains of the patients with FTD-TDP-43, ALS, and FTD-ALS were found to be phosphorylated TDP-43 at 45 kDa through the use of immunoblot analysis.

Evaluation of proteinopathy hypothesis

Neurodegenerative central nervous system proteinopathies, together with Alzheimer’s disease, are characterized by the accumulation of misfolded protein aggregates. The aggregates can be divided into a soluble, fibrillar, oligomeric, and more significant, less soluble or insoluble form. The hypothesis proposes the provision of new insights into how misfolded protein aggregates can cause neurodegeneration.

Alzheimer’s disease is considered to have a wide range of highly stable misfolded protein aggregates as compared to non –self and chronically activate the innate immune system of the other neurodegenerative proteinopathies. The physiological senescence of the central nervous system is led by the pro-inflammatory state. The physiological senescence of the central nervous system leads to the secretion of a variety of pro-inflammatory molecules. Hence the senescence of cells that was triggered by inflammatory stimuli turns to reinforce stimulus for further inflammation and senescence, which leads to brain organ failure.

The interrogative hypothesis is called proteinopathy –induced senescence cell hypothesis of neurodegenerative diseases that link central nervous system proteinopathy to cell dysfunction, inflammation, ultimately neurodegeneration and physiological senescence.

Conclusion.

Striping of individual cognitive power, functional capacity, and autonomy, as well as increasing dependence on others, are some of the effects of neurodegenerative diseases. These diseases pose a significant existential threat to the society in its strive to provide high quality and meaningful life to the aging citizens. According to the classical view, neurodegenerative disorders emphasized, behavioral changes, the definable clinical syndrome of neurological deficits, progressive functional decline and underpinned by inexorable neuronal loss