Neurodegenerative disease

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For the medical journal, see Experimental Neurology.
Neurodegenerative disease
Normal brain on left contrasted with structural changes shown in brain on right of person with Alzheimer's disease, the most common neurodegenerative disease[1]
SpecialtyNeurology, Psychiatry

A neurodegenerative disease is caused by the progressive loss of structure or function of

subcellular level, including atypical protein assemblies (like proteinopathy) and induced cell death.[6][7] These similarities suggest that therapeutic
advances against one neurodegenerative disease might ameliorate other diseases as well.

Within neurodegenerative diseases, it is estimated that 55 million people worldwide had dementia in 2019, and that by 2050 this figure will increase to 139 million people.[8]

Specific disorders

The consequences of neurodegeneration can vary widely depending on the specific region affected, ranging from issues related to movement to the development of dementia.[9][10]

Alzheimer's disease

Comparison of brain tissue between healthy individual and Alzheimer's disease patient, demonstrating extent of neuronal death
Main article: Alzheimer's disease

cingulate gyrus.[11] It is the most common neurodegenerative disease.[1] Even with billions of dollars being used to find a treatment for Alzheimer's disease, no effective treatments have been found.[12] However, clinical trials have developed certain compounds that could potentially change the future of Alzheimer's disease treatments.[13] Within clinical trials stable and effective AD therapeutic strategies have a 99.5% failure rate.[14] Reasons for this failure rate include inappropriate drug doses, invalid target and participant selection, and inadequate knowledge of pathophysiology of AD. Currently, diagnoses of Alzheimer's is subpar, and better methods need to be utilized for various aspects of clinical diagnoses.[15] Alzheimer's has a 20% misdiagnosis rate.[15]

AD pathology is primarily characterized by the presence of

beta secretase.[18] One of these fragments gives rise to fibrils of amyloid beta which can self-assemble into the dense extracellular amyloid plaques.[19][20]

Parkinson's disease

Main article: Parkinson's disease

bradykinesia
, rigidity, resting tremor and posture instability. The crude prevalence rate of PD has been reported to range from 15 per 100,000 to 12,500 per 100,000, and the incidence of PD from 15 per 100,000 to 328 per 100,000, with the disease being less common in Asian countries.

PD is primarily characterized by death of

Lewy bodies within affected neurons. It is thought that defects in protein transport machinery and regulation, such as RAB1, may play a role in this disease mechanism.[22] Impaired axonal transport of alpha-synuclein may also lead to its accumulation in Lewy bodies. Experiments have revealed reduced transport rates of both wild-type and two familial Parkinson's disease-associated mutant alpha-synucleins through axons of cultured neurons.[23] Membrane damage by alpha-synuclein could be another Parkinson's disease mechanism.[24]

The main known risk factor is age. Mutations in genes such as α-synuclein (SNCA),

gut microbiome might play a role in the diagnosis of PD, and research suggests various ways that could revolutionize the future of PD treatment.[27]

Huntington's disease

Main article: Huntington's disease

huntingtin gene (HTT). HD is characterized by loss of medium spiny neurons and astrogliosis.[28][29][30] The first brain region to be substantially affected is the striatum, followed by degeneration of the frontal and temporal cortices.[31] The striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder, notably chorea.[32] Huntington's disease presents itself later in life even though the proteins that cause the disease works towards manifestation from their early stages in the humans affected by the proteins.[33] Along with being a neurodegenerative disorder, HD has links to problems with neurodevelopment.[33]

HD is caused by

BDNF.[23] Huntington's disease currently has no effective treatments that would modify the disease.[34]

Multiple sclerosis

Main article: Multiple sclerosis

proteolipid protein, causing an autoimmune response.[36] This sets off a cascade of signaling molecules that result in T cells, B cells, and macrophages to cross the blood-brain barrier and attack myelin on neuronal axons leading to inflammation.[37] Further release of antigens drives subsequent degeneration causing increased inflammation.[38] Multiple sclerosis presents itself as a spectrum based on the degree of inflammation, a majority of patients experience early relapsing and remitting episodes of neuronal deterioration following a period of recovery. Some of these individuals may transition to a more linear progression of the disease, while about 15% of others begin with a progressive course on the onset of multiple sclerosis. The inflammatory response contributes to the loss of the grey matter, and as a result current literature devotes itself to combatting the auto-inflammatory aspect of the disease.[37] While there are several proposed causal links between EBV and the HLA-DRB1*15:01 allele to the onset of MS – they may contribute to the degree of autoimmune attack and the resultant inflammation – they do not determine the onset of MS.[37]

Amyotrophic lateral sclerosis

Main article:
Amyotrophic lateral sclerosis

Fused in Sarcoma (FUS) protein aggregates have been implicated in some cases of the disease, and a mutation in chromosome 9 (C9orf72) is thought to be the most common known cause of sporadic ALS. Early diagnosis of ALS is harder than with other neurodegenerative diseases as there are no highly effective means of determining its early onset.[39] Currently, there is research being done regarding the diagnosis of ALS through upper motor neuron tests.[40] The Penn Upper Motor Neuron Score (PUMNS) consists of 28 criteria with a score range of 0–32.[40] A higher score indicates a higher level of burden present on the upper motor neurons.[40] The PUMNS has proven quite effective in determining the burden that exists on upper motor neurons in affected patients.[40]

Independent research provided in vitro evidence that the primary cellular sites where SOD1 mutations act are located on

motor neurons. The specific mechanism of toxicity still needs to be investigated, but the findings are significant because they implicate cells other than neuron cells in neurodegeneration.[43]

Batten disease

Main article: Batten disease

lysosomal storage disorders known as neuronal ceroid lipofuscinoses (NCLs) – each caused by a specific gene mutation,[44] of which there are thirteen.[45] Since Batten disease is quite rare, its worldwide prevalence is about 1 in every 100,000 live births.[46] In North America, CLN3 disease (juvenile NCL) typically manifests between the ages of 4 and 7.[47] Batten disease is characterized by motor impairment, epilepsy, dementia, vision loss, and shortened lifespan.[48] A loss of vision is common first sign of Batten disease.[47] Loss of vision is typically preceded by cognitive and behavioral changes, seizures, and loss of the ability to walk.[47] It is common for people to establish cardiac arrhythmias and difficulties eating food as the disease progresses.[47] Batten disease diagnosis depends on a conflation of many criteria: clinical signs and symptoms, evaluations of the eye, electroencephalograms (EEG), and brain magnetic resonance imaging (MRI) results.[46] The diagnosis provided by these results are corroborated by genetic and biochemical testing.[46] No effective treatments were available to prevent the disease from being widespread before the past few years.[46] In recent years, more models have been created to expedite the research process for methods to treat Batten disease.[46]

Creutzfeldt–Jakob disease

Main article:
Creutzfeldt-Jakob disease

Creutzfeldt–Jakob disease (CJD) is a prion disease that is characterized by rapidly progressive dementia.[49] Misfolded proteins called prions aggregate in brain tissue leading to nerve cell death.[50] Variant Creutzfeldt–Jakob disease (vCJD) is the infectious form that comes from the meat of a cow that was infected with bovine spongiform encephalopathy, also called mad cow disease.[51]

Risk factor

Further information: Aging brain

The greatest risk factor for neurodegenerative diseases is aging. Mitochondrial DNA mutations as well as oxidative stress both contribute to aging.[52] Many of these diseases are late-onset, meaning there is some factor that changes as a person ages for each disease.[6] One constant factor is that in each disease, neurons gradually lose function as the disease progresses with age. It has been proposed that DNA damage accumulation provides the underlying causative link between aging and neurodegenerative disease.[53][54] About 20–40% of healthy people between 60 and 78 years old experience discernable decrements in cognitive performance in several domains including working, spatial, and episodic memory, and processing speed.[55]

Risks from viral exposures according to one biobank study[56]

A study using electronic health records indicates that 45 (with 22 of these being replicated with the UK Biobank) viral exposures can significantly elevate risks of neurodegenerative disease, including up to 15 years after infection.[56][57]

Mechanisms

Genetics

See also: Trinucleotide repeat disorder and Epigenetics of neurodegenerative diseases

Many neurodegenerative diseases are caused by

genetic mutations, most of which are located in completely unrelated genes. In many of the different diseases, the mutated gene has a common feature: a repeat of the CAG nucleotide triplet. CAG codes for the amino acid glutamine. A repeat of CAG results in a polyglutamine (polyQ) tract. Diseases associated with such mutations are known as trinucleotide repeat disorders.[58][59]

Polyglutamine repeats typically cause dominant pathogenesis. Extra glutamine residues can acquire toxic properties through a variety of ways, including irregular protein folding and degradation pathways, altered subcellular localization, and abnormal interactions with other cellular proteins.[58] PolyQ studies often use a variety of animal models because there is such a clearly defined trigger – repeat expansion. Extensive research has been done using the models of nematode (C. elegans), and fruit fly (Drosophila), mice, and non-human primates.[59][60]

Nine inherited neurodegenerative diseases are caused by the expansion of the CAG trinucleotide and polyQ tract, including Huntington's disease and the spinocerebellar ataxias.[61]

Epigenetics

The presence of epigenetic modifications for certain genes has been demonstrated in this type of pathology. An example is FKBP5 gene, which progressively increases its expression with age and has been related to Braak staging and increased tau pathology both in vitro and in mouse models of AD.[62]

Protein misfolding

See also: Stress granule

Several neurodegenerative diseases are classified as

proteopathies as they are associated with the aggregation of misfolded proteins. Protein toxicity is one of the key mechanisms of many neurodegenrative diseases.[63]

Intracellular mechanisms

Protein degradation pathways

Parkinson's disease and Huntington's disease are both late-onset and associated with the accumulation of intracellular toxic proteins. Diseases caused by the aggregation of proteins are known as

proteopathies, and they are primarily caused by aggregates in the following structures:[6]

There are two main avenues eukaryotic cells use to remove troublesome proteins or organelles:

Membrane damage

Damage to the membranes of organelles by monomeric or oligomeric proteins could also contribute to these diseases. Alpha-synuclein can damage membranes by inducing membrane curvature,[24] and cause extensive tubulation and vesiculation when incubated with artificial phospholipid vesicles.[24] The tubes formed from these lipid vesicles consist of both micellar as well as bilayer tubes. Extensive induction of membrane curvature is deleterious to the cell and would eventually lead to cell death. Apart from tubular structures, alpha-synuclein can also form lipoprotein nanoparticles similar to apolipoproteins.

Mitochondrial dysfunction

The most common form of cell death in neurodegeneration is through the intrinsic mitochondrial apoptotic pathway. This pathway controls the activation of caspase-9 by regulating the release of cytochrome c from the mitochondrial intermembrane space. Reactive oxygen species (ROS) are normal byproducts of mitochondrial respiratory chain activity. ROS concentration is mediated by mitochondrial antioxidants such as manganese superoxide dismutase (SOD2) and glutathione peroxidase. Over production of ROS (oxidative stress) is a central feature of all neurodegenerative disorders. In addition to the generation of ROS, mitochondria are also involved with life-sustaining functions including calcium homeostasis, PCD, mitochondrial fission and fusion, lipid concentration of the mitochondrial membranes, and the mitochondrial permeability transition. Mitochondrial disease leading to neurodegeneration is likely, at least on some level, to involve all of these functions.[64]

There is strong evidence that mitochondrial dysfunction and oxidative stress play a causal role in neurodegenerative disease pathogenesis, including in four of the more well known diseases

amyotrophic lateral sclerosis.[52]

Neurons are particularly vulnerable to oxidative damage due to their strong metabolic activity associated with high transcription levels, high oxygen consumption, and weak antioxidant defense.[65][66]

DNA damage

The brain metabolizes as much as a fifth of consumed oxygen, and

ataxia telangiectasia, Cockayne syndrome, Parkinson's disease and xeroderma pigmentosum.[68][67]

Axonal transport

Main article: Axonal transport

Axonal swelling, and

mitochondria.[23] When axonal transport is severely disrupted a degenerative pathway known as Wallerian-like degeneration is often triggered.[69]

Programmed cell death

Programmed cell death (PCD) is death of a cell in any form, mediated by an intracellular program.[70] This process can be activated in neurodegenerative diseases including Parkinson's disease, amytrophic lateral sclerosis, Alzheimer's disease and Huntington's disease.[71] PCD observed in neurodegenerative diseases may be directly pathogenic; alternatively, PCD may occur in response to other injury or disease processes.[7]

Apoptosis (type I)

Apoptosis is a form of programmed cell death in multicellular organisms. It is one of the main types of programmed cell death (PCD) and involves a series of biochemical events leading to a characteristic cell morphology and death.

Caspases (cysteine-aspartic acid proteases) cleave at very specific amino acid residues. There are two types of caspases: initiators and effectors. Initiator caspases cleave inactive forms of effector caspases. This activates the effectors that in turn cleave other proteins resulting in apoptotic initiation.[7]

Autophagic (type II)

Autophagy is a form of intracellular phagocytosis in which a cell actively consumes damaged organelles or misfolded proteins by encapsulating them into an autophagosome, which fuses with a lysosome to destroy the contents of the autophagosome. Because many neurodegenerative diseases show unusual protein aggregates, it is hypothesized that defects in autophagy could be a common mechanism of neurodegeneration.[7]

Cytoplasmic (type III)

PCD can also occur via non-apoptotic processes, also known as Type III or cytoplasmic cell death. For example, type III PCD might be caused by trophotoxicity, or hyperactivation of trophic factor receptors. Cytotoxins that induce PCD can cause necrosis at low concentrations, or aponecrosis (combination of apoptosis and necrosis) at higher concentrations. It is still unclear exactly what combination of apoptosis, non-apoptosis, and necrosis causes different kinds of aponecrosis.[7]

Transglutaminase

ubiquitously present in the human body and in the brain in particular.[73]

The main function of transglutaminases is

covalent bonds termed isopeptide bonds, in a reaction termed transamidation or crosslinking.[73]

Transglutaminase binding of these proteins and peptides make them clump together. The resulting structures are turned extremely resistant to chemical and mechanical disruption.[73]

Most relevant human neurodegenerative diseases share the property of having abnormal structures made up of proteins and peptides.[73]

Each of these neurodegenerative diseases have one (or several) specific main protein or peptide. In

Huntington's disease, it is huntingtin.[73]

Transglutaminase substrates:

covalent bonds to each other and potentially to any other transglutaminase substrate in the brain.[73]

Transglutaminase augmented expression: It has been proved that in these neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and Huntington's disease) the expression of the transglutaminase enzyme is increased.[73]

Presence of isopeptide bonds in these structures: The presence of isopeptide bonds (the result of the transglutaminase reaction) have been detected in the abnormal structures that are characteristic of these neurodegenerative diseases.[73]

Co-localization: Co-localization of transglutaminase mediated isopeptide bonds with these abnormal structures has been detected in the autopsy of brains of patients with these diseases.[73]

Management

The process of neurodegeneration is not well understood, so the diseases that stem from it have, as yet, no cures.

Animal models in research

In the search for effective treatments (as opposed to

Dimebon by Medivation, Inc. In 2009 this drug was in phase III clinical trials for use in Alzheimer's disease, and also phase II clinical trials for use in Huntington's disease.[59] In March 2010, the results of a clinical trial phase III were released; the investigational Alzheimer's disease drug Dimebon failed in the pivotal CONNECTION trial of patients with mild-to-moderate disease.[74] With CONCERT, the remaining Pfizer and Medivation Phase III trial for Dimebon (latrepirdine) in Alzheimer's disease failed in 2012, effectively ending the development in this indication.[75]

In another experiment using a rat model of Alzheimer's disease, it was demonstrated that systemic administration of hypothalamic proline-rich peptide (PRP)-1 offers neuroprotective effects and can prevent neurodegeneration in hippocampus

amyloid-beta 25–35. This suggests that there could be therapeutic value to PRP-1.[76]

Other avenues of investigation

Protein degradation offers therapeutic options both in preventing the synthesis and degradation of irregular proteins. There is also interest in upregulating autophagy to help clear protein aggregates implicated in neurodegeneration. Both of these options involve very complex pathways that we are only beginning to understand.[6]

The goal of immunotherapy is to enhance aspects of the immune system. Both active and passive vaccinations have been proposed for Alzheimer's disease and other conditions; however, more research must be done to prove safety and efficacy in humans.[77]

A current therapeutic target for the treatment of Alzheimer's disease is the protease β-secretase[78][non-primary source needed], which is involved in the amyloidogenic processing pathway that leads to the pathological accumulation of proteins in the brain. When the gene that encodes for amyloid precursor protein (APP) is spliced by α-secretase[79][non-primary source needed] rather than β-secretase, the toxic protein β amyloid is not produced. Targeted inhibition[80] of β-secretase can potentially prevent the neuronal death that is responsible for the symptoms of Alzheimer's disease.

Dr. Antonio Barbera, a former obstetrics and gynaecology doctor, is prescribing table tennis for patients who are suffering from a serious neurological disorder.[81]

See also

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