Neurodegenerative diseases

Refers to a group class of disorders characterized by progressive neuronal death leads to debilitating neurologic impairment.

Includes Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s chorea and multiple systems atrophy.

Neurodegenerative diseases are commonly adult onset conditions characterized by degeneration of specific populations of neurons.

Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease are all characterized by the progressive loss of neurons, cognitive decline, motor impairments, and sensory loss: proteinopathies due to the common assemblage of misfolded or aggregated intracellular or extracellular proteins. 

Some neurodegenerative diseases are caused by mutations in single genes, but most patients have a sporadic form that lacks a specific correlation in a mutation.

Many neurodegenerative diseases have abnormal protein aggregates with unique molecular composition for each type disease.

Aberrant messenger RNA translation is implicated in many neurodegenerative diseases: Alzheimer’s disease, frontotemporal dementia, Parkinson’s, disease, Huntington’s disease, prion, disease, ALS, spinal muscle atrophy, and Charcot Marie tooth disease.

Mortality from neurodegenerative diseases is higher and prescriptions for dementia related problems are more common among former professional soccer players than among controls in a Scottish population.

Neurodegeneration refers to the progressive loss of structure or function of neurons, including death of neurons.

Neurodegenerative diseases are incurable, resulting in progressive degeneration and/or death of neuron cells.

Parallels between different neurodegenerative disorders occur including  atypical protein assemblies as well as induced cell death.

Neurodegeneration occurs in many different levels of neuronal circuitry ranging from molecular to systemic.

Alzheimer’s disease is characterized by loss of neurons and synapses in the cerebral cortex and some subcortical regions.

The loss of neurons results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.

Alzheimer’s disease proposed  to be a protein misfolding disease, caused by accumulation of abnormally folded A-beta and tau proteins in the brain.

Alzheimer’s disease plaques are made up of small peptides, 39–43 amino acids in length, called beta-amyloid.

Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP).

Amyloid precursor transmembrane protein is  that penetrates through the neuron’s membrane.

The amyloid precursor protein (APP) is critical to neuron growth, survival and post-injury repair.

In Alzheimer’s disease, amyloid precursor protein is divided into smaller fragments by enzymes through proteolysis.

One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques.

Parkinson’s disease is the second most common neurodegenerative disorder.

Parkinson’s disease results from degenerating cells in the substantia nigra, a region of the midbrain.

In Parkinson’s disease there is an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells.

This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies.

The death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles – the endoplasmic reticulum (ER) and the Golgi apparatus.

It is likely impaired axonal transport of alpha-synuclein leads to its accumulation in the Lewy bodies.

The main known risk factor for Parkinson’s disease is age.

Susceptibility genes including α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase have shown that genetic predisposition is another important causal factor in Parkinson’s disease.

Huntington disease causes astrogliosis and loss of medium spiny neurons.

In Huntington’s  chorea the areas of the brain are affected according to their structure and the types of neurons they contain.

Brain structures decrease  in size as they cumulatively lose cells.

In Huntington’s  chorea the areas affected are mainly in the striatum, but also the frontal and temporal cortices

The striatum’s subthalamic nuclei send control signals to the globus pallidus.

The globus pallidus initiates and modulates motion.

Because of weaker signals from subthalamic nuclei reduced initiation and modulation of movement occurs and results in the characteristic movements of the disorder, chorea.

Mutant Huntingtin is an aggregate-prone protein, which  are retrogradely transported to the cell body for destruction by lysosomes.

These mutant protein aggregates may damage the retrograde transport of important cargoes, by damaging molecular motors as well as microtubules.

Amyotrophic lateral sclerosis is a disease in which motor neurons are selectively targeted for degeneration.

Missense mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) were discovered in a subsets of patients with familial ALS.

TDP-43 and 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.

The primary cellular sites where SOD1 mutations act are located on astrocytes, which then cause the toxic effects on the motor neurons.

The greatest risk factor for neurodegenerative diseases is progressive age.

Mitochondrial DNA mutations as well as oxidative stress both contribute to aging.

Most neurodegenerative diseases are late-onset, and neurons gradually lose function as the disease progresses with age.

It is suggested DNA damage accumulation provides the underlying causative link between aging and neurodegenerative disease.

20-40% of people between 60 and 78 years old experience decrements in cognitive performance in several domains including working, spatial, and episodic memory, and processing speed.

Many neurodegenerative diseases are caused by genetic mutations.

These gene mutations are located in completely unrelated genes.

A common  mutated gene in a number of different diseases have a common feature, a repeat of the CAG  nucleotide triplet.

CAG encodes for the amino acid glutamine, and a repeat of CAG results in a polyglutamine tract.

Diseases showing repeats of CAG  are known as polyglutamine diseases.

Extra glutamine residues in polyglutamine states can acquire toxic properties, by including irregular protein folding and degradation pathways, altered subcellular localization, and abnormal interactions with other cellular proteins.

Nine inherited neurodegenerative diseases are caused by the expansion of the CAG trinucleotide and polyQ tract.

Some neurodegenerative diseases are classified with the aggregation of misfolded proteins-proteopathies.

Alpha-synuclein aggregates form insoluble fibrils  characterized by Lewy bodies, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy.

Alpha-synuclein is the primary structural component of Lewy body fibrils.

An alpha-synuclein fragment, known as the non-Abeta component is found in amyloid plaques in Alzheimer’s disease.

tau protein is the main component of neurofibrillary tangles in Alzheimer’s disease.

beta amyloid is the major component of senile plaques in Alzheimer’s disease.

prions are the major component of prion diseases and transmissible spongiform encephalopathies.

Parkinson’s disease and Huntington’s disease are both associated with the accumulation of intracellular toxic proteins, known as proteinopathies.

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

ubiquitin–proteasome enzymes that can degrade many proteins that cause proteinopathies-including polyQ expansions and alpha-synucleins.

Proteasome enzymes may not be able to correctly cleave these irregular proteins, result in a more toxicity.

Decreased proteasome activity is consistent with how intracellular protein aggregates form.

The most common form of cell death in neurodegenerative disease  is through the mitochondrial apoptotic pathway.

Reactive oxygen species (ROS) are normal byproducts of mitochondrial respiratory chain activity, and their concentration is mediated by mitochondrial antioxidants such as manganese superoxide dismutase (SOD2) and glutathione peroxidase.

Oxidative stress, an over production of ROS is a central feature of all neurodegenerative disorders.

Mitochondrial dysfunction and oxidative stress play a causal role in neurodegenerative disease pathogenesis and include: Alzheimer’s, Parkinson’s, Huntington’s, and Amyotrophic lateral sclerosis.

Neurons are known to be  vulnerable to oxidative damage due to their strong metabolic activity associated with high transcription levels, high oxygen consumption, and weak antioxidant defense.

The brain metabolizes as much as a fifth of consumed oxygen, and reactive oxygen species produced by oxidative metabolism are a major source of DNA damage in the brain.

The vulnerability of neurons to DNA damage coupled with a gradual decline in the activities of repair mechanisms, could lead to accumulation of DNA damage with age and contribute to brain aging and neurodegeneration.

With the neurodegenerative disease ataxia-oculomotor apraxia DNA single-strand breaks are common .

DNA damage due to  oxidative disease in the brain is associated with Alzheimer’s disease and Parkinson’s disease.

Defective DNA repair has been linked to neurodegenerative disorders:Alzheimer’s  disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Parkinson’s disease and xeroderma pigmentosum.

Defective axons with atonal swelling, and axonal spheroids are seen  in many different neurodegenerative diseases.

Defective axons are present in diseased neurons, and may cause certain pathological insult due to accumulation of organelles.

When axonal transport is severely disrupted Wallerian-like degeneration is often triggered.

Programmed cell death (PCD) refers to death of a cell in any form, mediated by an intracellular program.

Neurodegenerative diseases including Parkinson’s disease, amytrophic lateral sclerosis, Alzheimer’s disease and Huntington’s disease undergo programmed cell death.

Programmed cell death mediated pathways can be artificially stimulated due to injury or disease.

Apoptosis is a form of programmed cell, and  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.

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

Each of these neurodegenerative disesases have one (or several) specific main protein or peptide;  In Alzheimer’s disease, these are amyloid-beta and tau. In Parkinson’s disease, it is alpha-synuclein. In Huntington’s disease, it is huntingtin.

Transglutaminase substrates: Amyloid-beta, tau, alpha-synuclein and huntingtin have been proved to be substrates of transglutaminases in vitro or in vivo, that is, they can be bonded by trasglutaminases by covalent bonds to each other and potentially to any other transglutaminase substrate in the brain.

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.

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.

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.








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