Neurodegeneracy

Abstract

Despite its vulnerability to neurodegenerative diseases, the neuromuscular junction has developed powerful ways to withstand injury and regenerate. Individuals with neurodegenerative diseases have a shorter life expectancy. Most existing treatments for neurodegenerative diseases only address symptoms. In order to limit the harmful effects, it is important to develop successful therapies to setback the symptoms of these debilitating diseases. Though some neurodegenerative disorders are fatal, most lead to health complications that are associated with high mortality rates. Although this difference might be a matter of semantics, we consider it significant, not only for managing the patient but also for our understanding of the actual consequences of the neurodegenerative process.

1. Introduction

Neurodegeneration describes a complex and serious medical condition, which principally affects the neurons. Such a situation leads to disorders of the central nervous system.

Degenerative nerve affects various body activities such as balance, movement, talking, heart functioning, breathing, mood swing, poor coordination, seizure, confusion, and altered levels of consciousness in other words it affects day-to-day life. The basis of such dysfunction can be quite varied.

Neurological disorders can influence the entire neurologic pathway or a single neuron. Even a little disturbance to a neuron’s structural pathway can result in dysfunction.

Neurological disorders can result from a number of sources that includes lifestyle, nutrition, environmental influences, physical injuries, infections including defective protein degradation and aggregation, free radical formation, oxidative stress and exposure to metal toxicity and pesticides.

The central nervous system consists of two types of cells, neurons and glial cells. Electrical impulses are not produced by glial cells, they are the supporting cells of neurons. These glial cells are superior to neurons in their function and cellular diversity. Glial cells including microglia, oligodendrocytes, and astrocytes, can regulate neuronal action.

Typically, the development of neurodegeneration initiates in the subcortical region as the disease progresses and extends to cortical regions [1]. Primary loss of neurons varies with the disease like striatal and cortical regions in HD, striatal regions in PD, spinal motor neurons and cortical regions in ALS, and hippocampal and cortical regions in AD [2, 3, 4].

Neurodegenerative diseases consider sharing a common pathogenic mechanism relating to aggregation and deposition of misfolded proteins, leading to unavoidable progressive worsening of the central nervous system. Misfolded proteins may create the most trouble as they form protofibrils. A number of methods have been described. In a few cases, these are particularly related to the type of protein, but in many other cases, they are nonspecific mechanisms shared by every misfolded protein disease. For a normal function, a protein must be properly synthesised and folded into its normal three-dimensional configuration. Nascent proteins are served in folding by molecular chaperones. Improperly folded proteins either damaged or otherwise beyond their functional lives are degraded by a ubiquitin-dependent proteasome protein degradation system.

In this system initially, the proteins are labelled for degradation by attachment of a polyubiquitin chain. Protein fragments and polyubiquitin are the end products of proteasome action. This polyubiquitin is then degraded and also recycled to the cellular ubiquitin pool, this process required enzymatic action by ubiquitin carboxy-terminal hydrolase 1.

The subject of strong investigation is the cascade of pathogenic actions linking abnormal protein aggregation to cell death. Even though aggregates are the most striking physical change in surviving cells, the actual function of the aggregate remains a mystery. Mostly it is believed that the formation of aggregates may be a protective mechanism sequestering the wayward protein from vulnerable cell procedure.

There is an emerging proof that performed fibrils generated from the full length and truncated recombinant α-synuclein enter neurons, most likely by endocytosis, and act as “seeds” that stimulate the employment of soluble endogenous α-synuclein into soluble inclusions, resulting in progressive prion-like extend of neurodegeneration. The mutant protein may not be able to carry out a vital function or may obstruct the function of the wild-type protein. Mutant proteins may operate the apoptotic cascade. They may impede intracellular transport or other vital activities. They may restrain the activity of the proteasome, increasing protein aggregation. They may get in the way of mitochondrial function, making cells more exposed to excitotoxicity. Lysosomes play an essential role in ubiquitin–proteasome system in degrading intracellular proteins. When the function of the ubiquitin-proteasome system is not enough to clear the accumulating cellular protein, then the autophagy-lysosome pathway turns into the other main direction for the degradation of misfolded proteins as well as unwell mitochondria. For maintaining cellular health mitophagy is a highly recognised mechanism.

With the ageing of the population, the occurrence of neurodegeneration is escalating spectacularly in the absence of either effective therapeutic involvement or a clear understanding of the separate pathophysiology of neurodegenerative disease states.

Currently, a few hundred neurodegenerative diseases have been estimated and among these, many appear to overlap with one another pathologically and clinically, leaving their practical categorisation challenging to a certain extent. In diseases the issue is further complicated by multisystem atrophy where quite a lot of areas of the brain are affected, different combinations of lesions can give different clinical pictures. Moreover, the same neurodegenerative processes, in particular at the beginning, can affect different areas of the brain, making a known given disease appear very different from a symptomatic standpoint. In spite of these difficulties, the most popular classification of neurodegenerative disorders is still o the bases of the predominant clinical feature or the topography of the predominant lesion, or frequently on a combination of both.

2. Sleep and neurodegeneration

Dementia is described by a progressive decline of reminiscence and cognition followed by language dysfunction, depression, hallucinations, other psychotic features, and sleep disturbance. In advanced phases, the patient turns out to be mute, bedridden and incontinent. The chief sleep disturbances in dementing illness include hypersomnia, insomnia, extreme nocturnal motor action, circadian sleep/wake rhythm disorders, respiratory dysrhythmias and “sundowning”.

Synthesis of new extracellular matrix protein takes place in reactive astrocytes in the areas of neural degeneration that provide boundaries to segregate damaged axons from healthy axons, prevent hematogenous cells from invading the offended neural tissues, affect the survival of remaining axons, and prevent axonal regrowth.

3. Classification and molecular characteristics of neurotraumatic disease

Neurodegeneration is a complex multifactorial progression that causes neuronal death in the brain and spinal cord, resulting in brain and spinal cord injury and dysfunction. Neurodegeneration along with axonal transport shortage, oxidative stress, protein oligomerization, aggregation, mitochondrial dysfunction, calcium deregulation, DNA damage, irregular neuron-glial interactions, neuroinflammation and abnormal RNA processing.

Neurodegeneration happens in neurotraumatic, neurodegenerative, and neuropsychiatric diseases. These diseases occur due to neurochemical, structural and electrophysiological aberrations in the brain, spinal cord, and nerve bringing out muscle weakness, paralysis, seizures, uncertainty, poor coordination and soreness. Neurodegenerative diseases entail the accretion of misfolded proteins and the beginning of neurodegenerative diseases, some nutrients, oxygen and ATP are accessible to the neurons, ion homeostasis is maintained to a limited point, and neurodegeneration takes a longer time to die.

Neuropsychiatric disorders are schizophrenia, depression, autism, bipolar effective disorders, attention-deficit disorder, tardive dyskinesia, and chronic fatigue syndrome.

Neurodegeneration encircles multiple molecular ways and a complex interplay between different regulatory factors together with the epigenetic mechanism. Although traditional drugs target various etiological mechanisms in separation, one should concentrate on drugs which have multiple therapeutic objectives and can be given either as monotherapy or as adjunctive drugs for effective results.

4. Neurodegeneration with Brain Iron Accumulation (NBIA)

The latest molecular studies revealed the existence of inherited neurodegenerative disorders, termed “neurodegeneration with brain iron accumulation” (NBIA), owing to genetic faults associated with iron metabolism. NBIA is a heterogeneous set of disorders that comprises “Pantothenate Kinase-Associated Neurodegeneration” (PKAN), infantile neuroaxonal defect, and neuroferritinopathy. Together, these disorders share similarities in extrapyramidal neurodegeneration and focal Fe accumulation, frequently in the basal ganglia and further brain regions including the thalamus, SN, cerebellar dentate nucleus and red nucleus. Symptoms comprise disablement in movement and cognition. NBIA consists of a series of disorders, a few caused by a mutation in a well-distinguished metalloprotein.

Along with iron accumulation, lipid peroxidation and mitochondrial damage are involved in both NBIA and ferroptosis, signifying the role of ferroptosis in the development of neurodegenerative diseases.

The general neurodegenerative diseases following TBI (Traumatic Brain Injury) resemble Parkinson’s disease (PD) and Alzheimer’s disease (AD) too share identical characteristics with ferroptosis, such as overload iron and lipid peroxidation.

Unique with iron excess syndromes, aceruloplasminemia (iron accumulation in the brain and other organs) involves together systemic and brain iron metabolism. A noticeable build-up of iron in the affected parenchymal tissues, namely the liver, pancreas, thyroid, and heart, the outcome in cardiac failure and hypothyroidism. The systemic tissues with access to iron are the reason for disrupted tissue iron release, followed by incorporation into circulating transferrin.

5. Neurological disorders

There are numerous distinguished neurological disorders, and a number of them are common, but many are rare. They may be evaluated by neurological assessment, studied and treated by the expertise of neuropsychology. Neurological disorders can be classified according to the primary affected area because the primary cause is most important and the wide division is between the central nervous system and peripheral nervous system disorders. Neurological disorders can influence the whole neurological pathway or a neuron alone. Even a little trouble with a neuron’s structural pathways can consequence in dysfunction.

There are numerous mechanisms of pathogenesis involved in the progress of neurodegenerative disorders. Internal and external stressors can cause activation of neuroglial cells which involves the disturbance of normal nervous functions and triggers the process of apoptosis in the neuronal cells. A small portion of neurodegenerative diseases are due to the mutation of disease-related genes, but the majority of them are sporadic where environmental issues and ageing plays a predominant role. Disturbance of cellular function from ageing- stimulates the accumulation of neuronal stressors resulting in cell death. Though, there is somewhat little neuronal loss in normal ageing, while cell death is a general characteristic of neurodegenerative diseases.

In the homeostatic regulation of physiological and pathological functions, redox balance plays an important role. When surplus free radicals cannot be eradicated, the accumulation stimulates and leads to “oxidative stress”. The reactive oxygen species (ROS) accumulation can cause damage to mitochondrial DNA, agitating the reliability of the energy cycle, which is necessary for neurological growth and function.

Neuronal tissue inflammation happens due to the accumulation of ROS, which encourages the synthesis of cytokines and other inflammatory mediators by triggering the inflammation pathway.

Antioxidant therapy represents an assuring possibility for the treatment of neurological diseases. Even though the difficulty and inconsistency of redox biology have mostly avoided the analysis of the mechanisms of and therapeutic approaches for neurological disease.

The lack of early diagnosis and cure for neurodegenerative diseases is always to be a huge confront for society.

6. Neurodegenerative disorders

6.1 Agnosia

In this disorder the ability to identify objects, persons, sound, shapes or smells are lost while the specific sense is neither defective nor is there any considerable memory loss. Usually, it is correlated with brain injury or neurological illness, especially after damage to the right parietal lobe.

6.2 Alexander disease

It is a gradually progressing and mortal neurodegenerative disease. It is an atypical disorder which results from a genetic mutation and generally has an effect on infants and children, causing developmental obstacles and changes once physical characteristics.

6.3 Alpers disease

A rare degenerative disease of the brain connecting the grey matter. It is described by the acute initiation of severe convulsions that lead to a speedy intellectual and bodily breakdown. Other features are deafness, myoclonus, blindness, choreoathetosis, spasticity, cerebellar ataxia, growth delay, plus terminal decortications. Noticeable in early childhood and generally causes death within a month.

6.4 Alzheimer’s disease

The disease of the brain progresses slowly and is characterised by the devastation of memory and ultimately disturbance in planning, language, reasoning and perception.

6.5 Apraxia

This neurological disorder is described by the loss of ability to perform learned determined movements, even though having the desire to perform the physical activities. It is a disorder of motor planning which may be obtained or developmental, but it is may not be caused by sensory loss, in coordination.

6.6 Batten disease

It begins in childhood, a rare, deadly, autosomal recessive neurodegenerative disorder. It is also known as “Spielmeyer-Vogt-Sjogren-Batten” disease, it is one of the most common forms of disorders called NCLs (neuronal ceroid lipofuscinosis).

6.7 Benign essential blepharospasm

It is a progressive neurological disorder differentiated by involuntary muscle contractions and spasms of the eyelid muscles.

6.8 Canavan disease

It is one of the most general cerebral degenerative diseases of infancy, is a gene-linked, neurological birth disorder where the white matter of the brain degenerates into spongy tissue puzzled with microscopic fluid that filled the spaces. This disease is known as leukodystrophy a group of genetic disorders, which cause faulty development or growth of myelin sheath, the fatty covering that work as an insulator around nerve fibres in the brain. Canavan disease is caused by a mutation in the gene used for an enzyme called aspartoacylase.

6.9 Cerebral beriberi

Also known as “Wernicke’s Encephalopathy” is a degenerative brain disorder due to the lack of Vit B1(thiamin). It may be the result of alcohol abuse, prolonged vomiting, eating disorders, and dietary deficiencies.

6.10 Corticobasal degeneration

A continuous neurological disorder described by nerve cell loss and shrinkage of multiple regions of the brain including the cerebral cortex and the basal ganglia, this progress gradually and initial symptoms begin around age 60.

6.11 Dementia

Also called “Semantic Frontotemporal Dementia” (FTD) shows a clinical syndrome linked with the shrinking of the frontal and temporal anterior lobes of the brain.

6.12 Hallervorden Spatz disease

Also Known as “Neurodegeneration with Brain Iron Accumulation” (NBIA) is an exceptional, inherited, neurological movement disorder describe by progressive degeneration of the nervous system.

6.13 Huntington’s disease

It is an inherited neurodegenerative disorder of the central nervous system, deteriorating and always fatal, this can cause progressive degeneration of cells in the brain, gradually weakening an individual’s ability to think, talk, walk and reason.

6.14 Lou Gehrig’s disease

Also known as “Amyotrophic Lateral Sclerosis” (ALS), a quickly progressive, constantly fatal neurological disease that attacks the neurons responsible for controlling voluntary muscle. In ALS the upper and lower motor neurons degenerate and stopping to send messages to muscles.

6.15 Mitochondrial myopathies

A group of neuromuscular diseases caused due to damage to the mitochondria, the energy-producing structures called the “powerhouse of the cell”. Neurons in the brain and muscles need a great deal of energy, this appears to be damaged when mitochondrial dysfunction occurs.

6.16 Neuronal Ceriod lipofuscinosis

This is the result of excessive accumulation of lipopigments in the body tissues. In general, it is the name for a family of at least eight genetically separate neurodegenerative disorders.

6.17 Neuronal migration disorders

These are the group of birth defects originating from the atypical migration of neurons in the developing brain and nervous system.

6.18 Olivopontocerebellar atrophy

The term (OPCA) is used to describe neurological degeneration in the cerebellum, pontine nuclei, and inferior olive. OPCA can also originate in the brains of an individual with prion disorders and inherited metabolic diseases. The distinctive regions of the damaged brain by OPCA can be seen by imaging the brain using CT scan or MRI studies.

6.19 O’Sullivan-McLeod syndrome

Also known as “Monomelic Amyotrophy” (MMA) and is illustrated by progressive degeneration and loss of motor neurons, the nerve cells of the brain and spinal cord, responsible for controlling voluntary muscles.

6.20 Paraneoplastic syndromes

It is a collection of rare degenerative disorders that are generated by a person’s immune system response to a neoplasm. It is believed to cause when cancer-fighting antibodies by mistake hit normal cells in the nervous system.

6.21 Pelizaeus-Merzbacher disease

It is a group of a gene linked to rare progressive, degenerative central nervous system disorders where motor skills, coordination and intellectual function deteriorate.

6.22 Prion disease

It is also known as “Transmissible Spongiform Encephalopathies” (TSEs), a rare group of degenerative brain disorders describe by minute holes that cause the brain a “spongy” appearance.

6.23 Sandhoff disease

It is caused due to the deficiency of the enzyme beta-hexosaminidase, which is the result of the accumulation of certain fats in the brain and other organs of the body. It is a rare, genetic disorder resulting in a progressive decline of the central nervous system.

6.24 Shy-Drager syndrome

It is a neurological disorder also known as multiple system atrophy with orthostatic hypotension causes dizziness and fainting. Doctors classify the disorder into 3 types

• Parkinsonian type includes symptoms of Parkinson’s disease.

• Cerebellar type causes problems with coordination and speech.

• The combined type includes symptoms of both parkinsonism and cerebellar failure.

It is a progressive disorder of the central and autonomic nervous systems were problems with urinary incontinence, weakness double vision, constipation and decreased sweating.

6.25 Tabes dorsalis

It is a slow degeneration of the nerve cells and nerve fibres that transmit sensory information to the brain. These nerves are in the dorsal columns of the spinal cord and carry out a signal which helps to maintain an individual’s sense of position.

7. Recent progress in preventing neurodegenerative diseases

It is known that neurological disorder which includes Alzheimer’s disease (AD), Multiple sclerosis (MS), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic lateral sclerosis (ALS) that noticeable in millions of people throughout the world every year. The common feature of these disorders is neuronal loss and the outcome is locomotor difficulties, cognitive defects, and chronic deterioration in memory.

Hence the researchers are following a collaborative approach to preserving the function and groups of neural tissues before the damage. This neuroprotective approach concentrates on the improvement in strategies that prevent most neuronal death.

8. Prevention of self-directed neurodegeneration

To maintain and restore physiological homeostasis cell has a variety of self-repair mechanism. Whenever a cell loses the capacity to overcome the damage, intracellular homeostasis falls and stimulates a series of cell death events takes place. Research over a few years and studies have shown that apoptotic cell death is not the only pathway directing the loss in these disorders. Among them, poly (ADP-ribose) (PAR)-dependent cell death has been started as being responsible for neuronal loss in various neurological disorders, comprising AD, ALS, HD, and PD. Oxidative stress injured DNA, resulting in PAR1 activation due to excessive accumulation of intracellular PARP1 [5]. Parthanatos is the result of numerous cellular processes, consisting release of apoptosis-inducing factor (AIF) from mitochondria, overactivation and macrophage migration inhibitory factor (MIF) and co-translocation of AIF into the nucleus, directing to DNA fragmentation and cell death [6, 7].

Overactivation of PARP1 and PAR accumulation have been noticed in the brains of AD patients [8, 9]. Studies have revealed that neurons are guarded by PARP1 inhibition, which means that PARP1 inhibition may have therapeutic importance for the treatment of AD.

Modern discoveries in the PD model show more direct facts that in pathologic α-synuclein neurodegeneration, parthanatos is the most important cell death pathway. In this PAR is the main mediator, encouraging α-synuclein toxicity and fibril conducting, exacerbating neurotoxicity in a feed-forward loop [10]. Oral administration of PARP1 inhibitor and genetic reduction of PARP1 stopped neurodegeneration and progresses motor capability in both genetic and sporadic models of PD [10, 11]. Moreover, increased PAR levels in the cerebral spinal fluid and brains of patients with PD [10], recommend that PARP1 might be a theragnostic biomarker and a disease-modifying therapeutic goal in PD [12]. Elongated polyglutamine (poly Q) is responsible for Huntington (htt) protein aggregation along with neuronal inclusions and toxicity in HD [13].

Enhanced PAR levels and dysregulation of PARP1 activation contribute to the pathogenesis of several neurodegenerative diseases by promoting parthanatos and protein aggregation. Therefore, a neuroprotective course of action intended to reduce PARP1 activation may have therapeutic potential in those disorders. Several well-described PARP inhibitors are in experimental use and yet to be tested for use in neurodegenerative disorders [14]. Thus these can be regarded as a neuroprotective treatment for neurological disorders.

9. Impede of non-cell-autonomous neurodegeneration

In neuronal support, glial cells play a key role in maintaining homeostasis, neurogenesis and nutrient transportation in healthy brains, [15]. Notably, an emerging research body has shown that dysfunctional non-neuronal cells such as astrocytes and microglia straight supply to neurodegeneration and cell death (Thus called non-cell autonomous neurodegeneration) in several neurodegenerative disorders.

Microglia are the inhabitant macrophages and primary immune cells in the brain. Hence they play a significant role in neuronal disease. In the post-mortem of AD brains, reactive microglia are present and have been shown to encourage synaptic drop and neuroinflammation [16, 17]. In the glial cells many PD-related genes, incorporating α-synuclein, PINK1, and parkin, are expressed. During PD pathogenesis mutated gene products are engaged in microglial dysfunction.

In review, microglia is believed to have both useful and harmful functions in neurodegenerative diseases. Therefore, the introduction of subsequent prevention of neurotoxic microglia signature and DAM (disease-associated microglia) or homeostatic microglia signature could be assuring therapeutic approaches for neuroprotection in neurodegenerative diseases, but the elements allied with heterogenous microglial phenotype will require to be defined in further detail.

The most abundant population of glial cells in the CNS is the astrocytes which carry out a broad range of homeostatic functions. So it is not surprising that the loss of the usual normal astrocyte role is engaged in the pathogenesis of neurodegenerative diseases. According to a 2017 investigation, activated microglia induce the formation of neurotoxic reactive astrocytes by releasing interleukin 1α (IL-1α), tumour necrosis factor α (TNF-α), and C1q [18]. In the post-mortem of the human brain, neurodegenerative diseases like AD, PD, ALS, and HD reactive astrocytes were found [18].

Currently, though, it has been observed that the phenotype variety of astrocytes is noticed in brains with neurodegenerative diseases and widens beyond the A1 and A2 phenotypes [19, 20, 21, 22, 23, 24]. Hence further research is required to know more about the molecular mechanisms of reactive astrocytes and their particular role within different neurodegenerative pathologies, specifically how the neurotoxic signals interchange and are shared across multiple neurodegenerative conditions.

10. Conclusion

There is a number of factors which cause neurodegenerative diseases such as neuronal cell death, genetic mutations, protein aggregation, flawed protein recycling, mitochondrial dysfunction, and innate immune responses due to glial cell activation. Hence neuroprotection can be achieved from cell-autonomous neurodegeneration directly by attacking their neighbouring cells. Thus, to prevent or slow neurodegeneration a multifaceted approach attacking both cell-autonomous and non-cell-autonomous mechanisms may be required.

To understand neurodegeneration, the molecular mechanism is an important footstep in the development of novel neuroprotective therapies. Due to remarkable efforts, these therapies have developed beyond the lab to the clinical testing stage. Thus, further research in the neurodegenerative pathways and the development and identification of neuroprotective agents are required to build up promising disease-modifying therapeutic approaches for the management, handling, and treatment of the neurodegenerative diseases.