Neurodegeneration | Wikipedia audio article

Neurodegeneration | Wikipedia audio article


Neurodegeneration is the progressive loss
of structure or function of neurons, including death of neurons. Many neurodegenerative diseases – including
amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, and Huntington’s
disease – occur as a result of neurodegenerative processes. Such diseases are incurable, resulting in
progressive degeneration and/or death of neuron cells. As research progresses, many similarities
appear that relate these diseases to one another on a sub-cellular level. Discovering these similarities offers hope
for therapeutic advances that could ameliorate many diseases simultaneously. There are many parallels between different
neurodegenerative disorders including atypical protein assemblies as well as induced cell
death. Neurodegeneration can be found in many different
levels of neuronal circuitry ranging from molecular to systemic.==Specific disorders=====
Alzheimer’s disease===Alzheimer’s disease is characterised by loss
of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss 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 has been hypothesized to be a protein
misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and
tau proteins in the brain. Plaques are made up of small peptides, 39–43
amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein
called amyloid precursor protein (APP), a transmembrane protein that penetrates through
the neuron’s membrane. APP is critical to neuron growth, survival
and post-injury repair. In Alzheimer’s disease, APP 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===Parkinson’s disease is the second most common
neurodegenerative disorder and manifests as 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. Parkinson’s disease is a degenerative disorder
of the central nervous system. It results from the death of dopamine-generating
cells in the substantia nigra, a region of the midbrain; the cause of cell-death is unknown. The following paragraph is an excerpt from
the Pathophysiology section of the article Parkinson’s disease. The mechanism by which the brain cells in
Parkinson’s are lost may consist of an abnormal accumulation of the protein alpha-synuclein
bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complex cannot
be directed to the proteasome. This protein accumulation forms proteinaceous
cytoplasmic inclusions called Lewy bodies. The latest research on pathogenesis of disease
has shown that 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. Certain proteins like Rab1 may reverse this
defect caused by alpha-synuclein in animal models.Recent research suggests that impaired
axonal transport of alpha-synuclein leads to its accumulation in the 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. Membrane damage by alpha-synuclein could be
another Parkinson’s disease mechanism.The main known risk factor is age. Susceptibility genes including α-synuclein,
leucine-rich repeat kinase 2 (LRRK-2), and glucocerebrosidase (GBA) have shown that genetic
predisposition is another important causal factor.===Huntington’s disease===The following paragraph is an excerpt from
the Mechanism section of the article Huntington’s disease. HD causes astrogliosis and loss of medium
spiny neurons. Areas of the brain are affected according
to their structure and the types of neurons they contain, reducing in size as they cumulatively
lose cells. 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, 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.Mutant Huntingtin is an aggregate-prone protein. During the cells’ natural clearance process,
these proteins are retrogradely transported to the cell body for destruction by lysosomes. It is a possibility that these mutant protein
aggregates damage the retrograde transport of important cargoes such as BDNF by damaging
molecular motors as well as microtubules.===Amyotrophic lateral sclerosis (ALS)===Amyotrophic lateral sclerosis (ALS or Lou
Gehrig’s disease) is a disease in which motor neurons are selectively targeted for degeneration. In 1993, missense mutations in the gene encoding
the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) were discovered in subsets of patients
with familial ALS. This discovery led researchers to focus on
unlocking the mechanisms for SOD1-mediated diseases. However, the pathogenic mechanism underlying
SOD1 mutant toxicity has yet to be resolved. More recently, 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. Recent independent research by Nagai et al.
and Di Giorgio et al. provide in vitro evidence that the primary cellular sites where SOD1
mutations act are located on astrocytes. Astrocytes then cause the toxic effects on
the 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.===Batten disease===
Batten disease is a rare and fatal recessive neurodegenerative disorder that begins at
birth.==Risk factor==
The greatest risk factor for neurodegenerative diseases is aging. Mitochondrial DNA mutations as well as oxidative
stress both contribute to aging. Many of these diseases are late-onset, meaning
there is some factor that changes as a person ages for each disease. 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. About 20-40% of healthy people between 60
and 78 years old experience discernable decrements in cognitive performace in several domains
including working, spatial, and episodic memory, and processing speed.==Mechanisms=====Genetics===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 encodes for the amino acid glutamine. A repeat of CAG results in a polyglutamine
(polyQ) tract. Diseases showing this are known as polyglutamine
diseases. Polyglutamine: A repeat in this causes 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. 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. Mammalian data is often needed for FDA approval
of drugs, which means that the bulk of the research is done using mice. Using data from the other animals (C. elegans
and Drosophila primarily) is often a precursor to finding the equivalent mammalian gene.Nine
inherited neurodegenerative diseases are caused by the expansion of the CAG trinucleotide
and polyQ tract. Two examples are Huntington’s disease and
the spinocerebellar ataxias. For a complete list, see the table under Polyglutamine
(PolyQ) Diseases in the article Trinucleotide repeat disorder. While polyglutamine-repeat diseases encompass
many different neurodegenerative disorders, there are many more it does not apply to. The genetics behind each disease are different
and often unknown.===Protein misfolding===
Several neurodegenerative diseases are classified as proteopathies as they are associated with
the aggregation of misfolded proteins. alpha-synuclein: can aggregate to form insoluble
fibrils in pathological conditions 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. In addition, an alpha-synuclein fragment,
known as the non-Abeta component (NAC), is found in amyloid plaques in Alzheimer’s disease. tau: hyperphosphorylated tau protein is the
main component of neurofibrillary tangles in Alzheimer’s disease. beta amyloid: the major component of senile
plaques in Alzheimer’s disease. prion: main component of prion diseases and
transmissible spongiform encephalopathies.===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 proteinopathies, and they are primarily caused by aggregates in the following
structures: cytosol, e.g. Parkinson’s & Huntington’s
nucleus, e.g. Spinocerebellar ataxia type 1 (SCA1)
endoplasmic reticulum (ER), (as seen with neuroserpin mutations that cause familial
encephalopathy with neuroserpin inclusion bodies)
extracellularly excreted proteins, amyloid-β in Alzheimer’s diseaseThere are two main avenues
eukaryotic cells use to remove troublesome proteins or organelles: ubiquitin–proteasome: protein ubiquitin
along with enzymes is key for the degradation of many proteins that cause proteinopathies
including polyQ expansions and alpha-synucleins. Research indicates proteasome enzymes may
not be able to correctly cleave these irregular proteins, which could possibly result in a
more toxic species. This is the primary route cells use to degrade
proteins.Decreased proteasome activity is consistent with models in which intracellular
protein aggregates form. It is still unknown whether or not these aggregates
are a cause or a result of neurodegeneration. autophagy–lysosome pathways: a form of programmed
cell death (PCD), this becomes the favorable route when a protein is aggregate-prone meaning
it is a poor proteasome substrate. This can be split into two forms of autophagy:
macroautophagy and chaperone-mediated autophagy (CMA).macroautophagy is involved with nutrient
recycling of macromolecules under conditions of starvation, certain apoptotic pathways,
and if absent, leads to the formation of ubiquinated inclusions. Experiments in mice with neuronally confined
macroautophagy-gene knockouts develop intraneuronal aggregates leading to neurodegeneration. chaperone-mediated autophagy defects may also
lead to neurodegeneration. Research has shown that mutant proteins bind
to the CMA-pathway receptors on lysosomal membrane and in doing so block their own degradation
as well as the degradation of other substrates.====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, and cause extensive tubulation and vesiculation when incubated with artificial
phospholipid vesicles.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
(IMS). 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.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 Alzheimer’s,
Parkinson’s, Huntington’s, and Amyotrophic lateral sclerosis.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.====DNA Damage====
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. Damage to a cell’s DNA is particularly harmful
because DNA is the blueprint for protein production and unlike other molecules it cannot simply
be replaced by re-synthesis. The vulnerability of post-mitotic neurons
to DNA damage (such as oxidative lesions or certain types of DNA strand breaks), 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. DNA single-strand breaks are common and are
associated with the neurodegenerative disease ataxia-oculomotor apraxia. Increased oxidative DNA damage in the brain
is associated with Alzheimer’s disease and Parkinson’s disease. Defective DNA repair has been linked to neurodegenerative
disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, ataxia telangiectasia,
Cockayne syndrome, Parkinson’s disease and xeroderma pigmentosum.====Axonal transport====
Axonal swelling and spheroids have been observed in many different neurodegenerative diseases. This suggests that defective axons are not
only present in diseased neurons, but also that they may cause certain pathological insult
due to accumulation of organelles. Axonal transport can be disrupted by a variety
of mechanisms including damage to: kinesin and cytoplasmic dynein, microtubules, cargoes,
and mitochondria. When axonal transport is severely disrupted
a degenerative pathway known as Wallerian-like degeneration is often triggered.===Programmed cell death===
Programmed cell death (PCD) is death of a cell in any form, mediated by an intracellular
program. This process can be activated in neurodegenerative
diseases including Parkinson’s disease, amytrophic lateral sclerosis, Alzheimer’s disease and
Huntington’s disease. There are, however, situations in which these
mediated pathways are artificially stimulated due to injury or disease.====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. Extrinsic apoptotic pathways: Occur when factors
outside the cell activate cell surface death receptors (e.g., Fas) that result in the activation
of caspases-8 or -10. Intrinsic apoptotic pathways: Result from
mitochondrial release of cytochrome c or endoplasmic reticulum malfunctions, each leading to the
activation of caspase-9. The nucleus and Golgi apparatus are other
organelles that have damage sensors, which can lead the cells down apoptotic pathways.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.====Autophagic (type II)====
Autophagy is essentially 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. Many neurodegenerative diseases show unusual
protein aggregates. This could potentially be a result of underlying
autophagic defect common to multiple neurodegenerative diseases. It is important to note that this is a hypothesis,
and more research must be done.====Cytoplasmic (type III)====
The final and least understood PCD mechanism is through non-apoptotic processes. These fall under Type III, or cytoplasmic
cell death. Many other forms of PCD are observed but not
fully understood or accepted by the scientific community. For example, PCD might be caused by trophotoxicity,
or hyperactivation of trophic factor receptors. In addition to this, other cytotoxins that
induce PCD at low concentrations act to cause necrosis, or aponecrosis – the combination
of apoptosis and necrosis, when in higher concentrations. It is still unclear exactly what combination
of apoptosis, non-apoptosis, and necrosis causes different kinds of aponecrosis.===PCD===
In the above-mentioned neurodegenerative diseases, PCD may be pathogenic. In order to identify the potential of neuroprotective
targets in PCD machinery, there were experimental models conducted on these neurodegenerative
diseases. These studies showed that the expression of
certain components have been altered by genetic and pharmacological means. Expression of PCD molecular components are
said to be controlled by gene and antisense therapy, but this needs further research. Pharmacological approaches involve inhibitors
of caspase activity, and caspase inhibition might delay cell death in the different experimental
models.===Transglutaminase===
Transglutaminases are human enzymes ubiquitously present in the human body and in the brain
in particular.The main function of transglutaminases is bind proteins and peptides intra- and intermolecularly,
by a type of covalent bonds termed isopeptide bonds, in a reaction termed transamidation
or crosslinking.Transglutaminase binding of these proteins and peptides make them clump
together. The resulting structures are turned extremely
resistant to chemical and mechanical disruption.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.==Management==
The process of neurodegeneration is not well understood, so the diseases that stem from
it have, as yet, no cures. In the search for effective treatments (as
opposed to palliative care), investigators employ animal models of disease to test potential
therapeutic agents. Model organisms provide an inexpensive and
relatively quick means to perform two main functions: target identification and target
validation. Together, these help show the value of any
specific therapeutic strategies and drugs when attempting to ameliorate disease severity. An example is the drug Dimebon (Medivation). This drug is in phase III clinical trials
for use in Alzheimer’s disease, and also recently finished phase II clinical trials for use
in Huntington’s disease. 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. 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.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.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.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.==See also==
Amyloids Dementia
JUNQ and IPOD Nervous system
Prevention of dementia Proteopathy
Trinucleotide repeat disorders

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