Para-sagittal MRI of the head in a patient with benign familial macrocephaly.Neurodegenerative disease
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
s are a heterogeneous group of complex disorders linked by the degeneration of
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s in either the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
or the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
. Their underlying causes are extremely variable and complicated by various genetic and/or environmental factors. These diseases cause progressive deterioration of the neuron resulting in decreased
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
and in some cases even neuronal death. Peripheral nervous system diseases may be further categorized by the type of nerve cell (
motor
An engine or motor is a machine designed to convert one or more forms of energy into mechanical energy.
Available energy sources include potential energy (e.g. energy of the Earth's gravitational field as exploited in hydroelectric power gen ...
,
sensory, or both) affected by the disorder. Effective treatment of these diseases is often prevented by lack of understanding of the underlying molecular and genetic pathology.
Epigenetic therapy
Epigenetic therapy is the use of drugs or other epigenome-influencing techniques to treat medical conditions. Many diseases, including cancer, heart disease, diabetes, and mental illnesses are influenced by epigenetic mechanisms. Epigenetic th ...
is being investigated as a method of correcting the expression levels of misregulated genes in neurodegenerative diseases.
Neurodengenerative diseases of motor neurons can cause degeneration of motor neurons involved in voluntary muscle control such as muscle contraction and relaxation. This article will cover the epigenetics and treatment of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). See th
Motor Neuron Fact Sheetfor details regarding other motor neuron diseases.
Neurodegenerative diseases of the central nervous system can affect the brain and/or
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
. This article will cover the epigenetics and treatment of
Alzheimer’s disease
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
(AD),
Huntington’s disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...
(HD), and
Parkinson’s disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
(PD). These diseases are characterized by chronic and progressive neuronal dysfunction, sometimes leading to behavioral abnormalities (as with PD), and, ultimately, neuronal death, resulting in
dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
.
Neurodegenerative diseases of sensory neurons can cause degeneration of sensory neurons involved in transmitting sensory information such as
hearing
Hearing, or auditory perception, is the ability to perceive sounds
In physics, sound is a vibration that propagates as an acoustic wave, through a transmission medium such as a gas, liquid or solid.
In human physiology and psycholog ...
and
seeing. The main group of sensory neuron diseases are hereditary sensory and autonomic neuropathies (HSAN) such as
HSAN I,
HSAN II, and
Charcot-Marie-Tooth Type 2B (CMT2B).
Though some sensory neuron diseases are recognized as neurodegenerative, epigenetic factors have not yet been clarified in the molecular pathology.
Epigenetics and epigenetic drugs
The term
epigenetics
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
refers to three levels of gene regulation: (1)
DNA methylation
DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts t ...
, (2)
histone modification
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn ar ...
s, and (3)
non-coding RNA
A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non-c ...
(ncRNA) function. Briefly, histone-mediated transcriptional control occurs by the wrapping of DNA around a
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
core. This DNA-histone structure is called a
nucleosome
A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamen ...
; the more tightly the DNA is bound by the nucleosome, and the more tightly a string of nucleosomes are compressed among each other, the greater the repressive effect on
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of genes in the DNA sequences near or wrapped around the histones, and vice versa (i.e. looser DNA binding and relaxed compaction leads to a comparatively derepressed state, resulting in facultative
heterochromatin
Heterochromatin is a tightly packed form of DNA or '' condensed DNA'', which comes in multiple varieties. These varieties lie on a continue between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role ...
or, even further derepressed,
euchromatin
Euchromatin (also called "open chromatin") is a lightly packed form of chromatin ( DNA, RNA, and protein) that is enriched in genes, and is often (but not always) under active transcription. Euchromatin stands in contrast to heterochromatin, whic ...
). At its most repressive state, involving many folds into itself and other scaffolding proteins, DNA-histone structures form constitutive heterochromatin. This chromatin structure is mediated by these three levels of gene regulation. The most relevant epigenetic modifications to treatment of neurodegenerative diseases are DNA methylation and histone protein modifications via methylation or acetylation.
*In mammals,
methylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
occurs on DNA and histone proteins.
DNA methylation
DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts t ...
occurs on the cytosine of
CpG dinucleotides in the genomic sequence, and protein methylation occurs on the amino termini of the core histone proteins - most commonly on lysine residues.
CpG refers to a dinucleotide composed of a cytosine deoxynucleotide immediately adjacent to a guanine deoxynucleotide. A cluster of CpG dinucleotides clustered together is called a
CpG island
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
, and in mammals, these CpG islands are one of the major classes of gene promoters, onto or around which transcription factors may bind and transcription can begin. Methylation of CpG dinucleotides and/or islands within gene promoters is associated with transcriptional repression via interference of
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
binding and recruitment of transcriptional repressors with methyl binding domains. Methylation of
intragenic regions is associated with increased transcription. The group of enzymes responsible for addition of methyl groups to DNA are called
DNA methyltransferase
In biochemistry, the DNA methyltransferase (DNA MTase, DNMT) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl m ...
s (DNMTs). The enzyme responsible for removal of methyl group are called DNA demethylases. The effects of
histone methylation
Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrea ...
are residue dependent (e.g. which amino acid on which histone tail is methylated) therefore the resulting transcriptional activity and
chromatin regulation can vary.
The enzymes responsible for the addition of methyl groups to histones are called
histone methyltransferases
Histone methyltransferases (HMT) are histone-modifying enzymes (e.g., histone-lysine N-methyltransferases and histone-arginine N-methyltransferases), that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues ...
(HMTs). The enzymes responsible for the removal of methyl groups from histone are
histone demethylases.
*
Acetylation
:
In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...
occurs on the lysine residues found at the amino N-terminal of histone tails. Histone acetylation is most commonly associated with relaxed chromatin, transcriptional derepression, and thus actively transcribed genes.
Histone acetyltransferases
Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
(HATs) are enzymes responsible for the addition of acetyl groups, and
histone deacetylase
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
s (HDACs) are enzymes responsible for the removal of acetyl groups. Therefore, the addition or removal of an acetyl group to a histone can alter the expression of nearby genes. The majority of drugs being investigated are inhibitors of proteins that remove acetyl from histones or histone deacetylases (HDACs).
*Briefly,
ncRNAs are involved in signaling cascades with epigenetic marking enzymes such as HMTs, and/or with
RNA interference
RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by o ...
(RNAi) machinery. Frequently these signaling cascades result in epigenetic repression (for one example, see
X-chromosome inactivation
X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into ...
), though there are some cases in which the opposite is true. For example, ''
BACE1-AS
''BACE1-AS'', also known as BACE1 antisense RNA ( non-protein coding), is a human gene at 11q23.3 encoding a long noncoding RNA molecule. It is transcribed from the opposite strand to ''BACE1'' and is upregulated in patients with Alzheimer's dis ...
'' ncRNA expression is upregulated in Alzheimer's disease patients and results in increased stability of ''
BACE1
Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is enco ...
'' - the mRNA precursor to an enzyme involved in Alzheimer's disease.
Epigenetic drugs target the proteins responsible for modifications on DNA or histone. Current epigenetic drugs include but are not limited to:
HDAC inhibitors
Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases.
HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are bei ...
(HDACi), HAT modulators, DNA methyltransferase inhibitors, and histone demethylase inhibitors.
The majority of epigenetic drugs tested for use against neurodegenerative diseases are HDAC inhibitors; however, some DNMT inhibitors have been tested as well. While the majority of epigenetic drug treatments have been conducted in mouse models, some experiments have been performed on human cells as well as in human drug trials (see table below). There are inherent risks in using epigenetic drugs as therapies for neurodegenerative disorders as some epigenetic drugs (e.g. HDACis such as
sodium butyrate
Sodium butyrate is a compound with formula Na(C3H7COO). It is the sodium salt of butyric acid. It has various effects on cultured mammalian cells including inhibition of proliferation, induction of differentiation and induction or repression ...
) are non-specific in their targets, which leaves potential for off-target epigenetic marks causing unwanted epigenetic modifications.
Neurodegenerative diseases of motor neurons
Amyotrophic lateral sclerosis (ALS)
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a motor neuron disease that involves neurogeneration. All skeletal muscles in the body are controlled by motor neurons that communicate signals from the brain to the muscle through a
neuromuscular junction
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
. When the motor neurons degenerate, the muscles no longer receive signals from the brain and begin to waste away. ALS is characterized by stiff muscles, muscle twitching, and progressive muscle weakness from muscle wasting. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first, usually the limbs. As the disease progresses most patients are unable to walk or use their arms and eventually develop difficulty speaking, swallowing and breathing. Most patients retain cognitive function and sensory neurons are generally unaffected. Patients are often diagnosed after the age of 40 and the median survival time from onset to death is around 3–4 years. In the final stages, patients can lose voluntary control of eye muscles and often die of
respiratory failure
Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...
or
pneumonia
Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severity ...
as a result of degeneration of the motor neurons and muscles required for breathing. Currently there is no cure for ALS, only treatments that may prolong life.
Genetics and underlying causes
To date, multiple genes and proteins have been implicated in ALS. One of the common themes between many of these genes and their causative mutations is the presence of
protein aggregates in motor neurons.
Other common molecular features in ALS patients are altered RNA metabolism
and general histone hypoacetylation.
![Human male karyotpe high resolution - Chromosome 21 cropped](https://upload.wikimedia.org/wikipedia/commons/6/6c/Human_male_karyotpe_high_resolution_-_Chromosome_21_cropped.png)
;SOD1:The
SOD1
Superoxide dismutase u-Znalso known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, Amyo ...
gene on
chromosome 21
Chromosome 21 is one of the 23 pairs of chromosomes in humans. Chromosome 21 is both the smallest human autosome and chromosome, with 48 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cells. ...
that codes for the superoxide dismutase protein is associated with 2% of cases and is believed to be transmitted in an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
manner.
Many different mutations in SOD1 have been documented in ALS patients with varying degrees of progressiveness. SOD1 protein is responsible for destroying naturally occurring, but harmful
superoxide radicals produced by the
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
. Most of the SOD1 mutations associated with ALS are gain-of-function mutations in which the protein retains its enzymatic activity, but aggregate in motor neurons causing toxicity.
Normal SOD protein is also implicated in other cases of ALS due to potentially cellular stress.
An ALS mouse model through gain-of-function mutations in SOD1 has been developed.
;c9orf72: A gene called
c9orf72
C9orf72 (chromosome 9 open reading frame 72) is a protein which in humans is encoded by the gene ''C9orf72''.
The human ''C9orf72'' gene is located on the short (p) arm of chromosome 9 open reading frame 72, from base pair 27,546,546 to base pai ...
was found to have a hexanucleotide repeat in the non-coding region of the gene in association with ALS and ALS-FTD.
These hexanucleotide repeats may be present in up 40% of familial ALS cases and 10% of sporadic cases. C9orf72 likely functions as a
guanine exchange factor for a small
GTPase
GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
, but this is likely not related to the underlying cause of ALS.
The hexanucleotide repeats are likely causing cellular toxicity after they are
spliced
Spliced may refer to:
*Spliced, the result of rope splicing
Rope splicing in ropework is the forming of a semi-permanent joint between two ropes or two parts of the same rope by partly untwisting and then interweaving their strands. Splices ca ...
out of the c9orf72 mRNA transcripts and accumulate in the nuclei of affected cells.
;UBQLN2: The
UBQLN2
Ubiquilin-2 is a protein that in humans is encoded by the ''UBQLN2'' gene.
Function
This gene encodes a ubiquitin-like protein ( ubiquilin) that shares high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain ...
gene encodes the protein ubiquilin 2 which is responsible for controlling the degradation of
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
ated proteins in the cell. Mutations in UBQLN2 interfere with protein degradation resulting in neurodegeneration through abnormal protein aggregation.
This form of ALS is X chromosome-linked and dominantly inherited and can also be associated with
dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
.
Epigenetic treatment with HDAC inhibitors
ALS patients and mouse models show general histone hypoacetylation that can ultimately trigger
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
of cells.
In experiments with mice, HDAC inhibitors counteract this hypoacetylation, reactivate aberrantly down-regulated genes, and counteract apoptosis initiation.
Furthermore, HDAC inhibitors are known to prevent SOD1 protein aggregates in vitro.
;Sodium phenylbutyrate:
Sodium phenylbutyrate
Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an ...
treatment in a SOD1 mouse model of ALS showed improved motor performance and coordination, decreased neural atrophy and neural loss, and increased weight gain.
Release of pro-apoptotic factors was also abrogated as well as a general increase in histone acetylation.
A human trial using phenylbuturate in ALS patients showed some increase in histone acetylation, but the study did not report whether ALS symptoms improved with treatment.
;Valproic scid:
Valproic acid
Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...
in mice studies restored histone acetylation levels, increased levels of pro-survival factors, and mice showed improved motor performance.
However, while the drug delayed the onset of ALS, it did not increase lifespan or prevent
denervation
Denervation is any loss of nerve supply regardless of the cause. If the nerves lost to denervation are part of the neuronal communication to a specific function in the body then altered or a loss of physiological functioning can occur. Denervation ...
.
Human trials of valproic acid in ALS patients did not improve survival or slow progression.
;Trichostatin A:
Trichostatin A
Trichostatin A (TSA) is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs (i.e., sirtuins). However, there are ...
trials in mouse ALS models restored histone acetylation in spinal neurons, decreased axon demyelination, and increased survival of mice.
Spinal Muscular Atrophy (SMA)
Alpha motor neurons are derived from the basal plate (basal lamina).
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by mutations in the
SMN1
Survival of motor neuron 1 (''SMN1''), also known as component of gems 1 or ''GEMIN1'', is a gene that encodes the SMN protein in humans.
Gene
''SMN1'' is the telomeric copy of the gene encoding the SMN protein; the centromeric copy is terme ...
gene.
Symptoms vary greatly with each subset of SMA and the stage of the disease. General symptoms include overall muscle weakness and poor muscle tone including extremities and respiratory muscles leading to difficulty walking, breathing, and feeding. Depending on the type of SMA, the disease can present itself from infancy through adulthood. As SMN protein generally promotes the survival of motor neurons, mutations in SMN1 results in slow degeneration motor neurons leading to progressive system-wide muscle wasting. Specifically, over time, decreased levels of SMN protein results in gradual death of the
alpha motor neuron
Alpha (α) motor neurons (also called alpha motoneurons), are large, multipolar lower motor neurons of the brainstem and spinal cord. They innervate extrafusal muscle fibers of skeletal muscle and are directly responsible for initiating their con ...
s in the
anterior horn of the spinal cord and brain. Muscles depend on connections to motor neurons and the central nervous system to stimulate muscle maintenance and therefore degeneration of motor neurons and subsequent denervation of muscles lead to loss of muscle control and muscle atrophy. The muscles of the lower extremities are often affected first followed by upper extremities and sometimes the muscles of respiration and mastication. In general, proximal muscle is always affected more than distal muscle.
Genetic cause
Spinal muscular atrophy is linked to genetic mutations in the SMN1 (Survival of Motor Neuron 1) gene. The SMN protein is widely expressed in neurons and serves many functions within neurons including
spliceosome
A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs (snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to specifi ...
construction, mRNA axon transport,
neurite
A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture ...
outgrowth during development, and
neuromuscular junction
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
formation. The causal function loss in SMA is currently unknown.
SMN1 is located in a
telomeric
A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
region of
human chromosome 5 and also contains SMN2 in a
centromeric
The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers ...
region. SMN1 and
SMN2
Survival of motor neuron 2 (''SMN2'') is a gene that encodes the SMN protein (full and truncated) in humans.
Gene
The ''SMN2'' gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four ge ...
are nearly identical except for a single
nucleotide change in SMN2 resulting in an alternative splicing site where intron 6 meets exon 8. This single base pair change leads to only 10-20% of SMN2 transcripts resulting in fully functional SMN protein and 80-90% of transcripts leading to a truncated protein that is rapidly degraded. Most SMA patients have 2 or more copies of the SMN2 gene with more copies resulting in a decrease in disease severity.
Most SMA patients have either
point mutation
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
s or a deletion in exon 7 often leading to a protein product similar to the truncated and degraded version of the SMN2 protein. In SMA patients this small amount of functional SMN2 protein product allows for some neurons to survive.
Epigenetic treatment through SMN2 gene activation
Although SMA is not caused by an epigenetic mechanism, therapeutic drugs that target epigenetic marks may provide SMA patients with some relief, halting or even reversing the progression of the disease. As SMA patients with higher copy numbers of the SMN2 gene have less severe symptoms, researchers predicted that epigenetic drugs that increased SMN2 mRNA expression would increase the amount of functional SMN protein in neurons leading to a reduction in SMA symptoms. Histone deacetylase (HDAC) inhibitors are the main compounds that have been tested to increase SMN2 mRNA expression. Inhibiting HDACs would allow for hyperacetylation of the SMN2 gene loci theoretically resulting in an increase in SMN2 expression.
Many of these HDAC inhibitors (HDACi) are first tested in mouse models of SMA created through a variety of mutations in the mouse SMN1 gene. If the mice show improvement and the drug does not cause very many side effects or toxicity, the drug may be used in human clinical trials. Human trials with all of the below HDAC inhibitors are extremely variable and often impacted by the patient's exact SMA subtype.
Myasthenia Gravis
Myasthenia gravis is an autoimmune disease affecting synapses at the neuromuscular junction, whereby antibodies produced primarily in the thymus gland by B-cells associate with postsynaptic nicotinic acetylcholine receptors (AChR), along with other NMJ post-synaptic receptors (MuSK-R and low-density lipoprotein receptor). These antibodies include acetylcholine receptor antibodies, MuSK antibodies, and low-density lipoprotein receptor related protein 4 antibodies (LRP4-Ab). Antibody binding to their respective receptors causes the destruction of those receptors, leading to a reduction in the number of postsynaptic acetylcholinergic receptors and a reduction in overall acetylcholine transport. Disease symptoms include muscular weakness that fatigues due to overuse, but improves with rest. Hallmark symptoms due to muscular weakness include ptosis, double vision, dysphagia, as well as aberrant speech.
Myasthenia gravis is a relatively rare disease, occurring in about 3-30 individuals per 100,000, but has been rising over the past couple decades. There exists two variations of myasthenia gravis with respect to age and gender demographics: early-onset myasthenia gravis, which has a higher incidence among females, and late-onset myasthenia gravis, which has a higher incidence among males.
Epigenetic Factors
There has been extensive research on the genetic basis of myasthenia gravis, however evidence does not suggest that it is an inherited disease. There has also been extensive research on the epigenetic contribution to myasthenia gravis. DNA methylation and noncoding RNA, such as miRNA (micro RNA) and long noncoding RNA (lncRNA), are epigenetic factors that play a significant role in increasing the likelihood of acquiring myasthenia gravis. In addition, the thymus is a key organ in the immune response that is often negatively affected by abnormal miRNA expression and DNA methylation.
miRNA
Micro RNA (miRNA) are single-stranded non-coding RNAs that bind their target mRNAs. From there, they can regulate gene expression by inhibiting translation or degrading the mRNA strand, oftentimes in B-cells and T-cells of the immunological process. With respect to myasthenia gravis, abnormal miRNA function is associated with immunoregulatory pathogenesis, and each miRNA has its own unique downstream effects.
The thymus is an important endocrine organ implicated in myasthenia gravis. In normal, healthy development, the thymus shrinks in size over time. In those with thymus-associated myasthenia gravis there are correlations with thymomas in late-onset myasthenia gravis as well as thymic hyperplasia with germinal centers in early-onset myasthenia gravis, and each of these conditions can be attributed partly to irregular miRNA function.
In late-onset myasthenia gravis subjects, it was shown that miRNA-12a-5p expression was increased in thymoma-associated myasthenia gravis. MiRNA-12a-5p inhibits expression of the gene FoxP3, a gene known to be associated with normal thymus development and whose alteration is attributed to thymomas.
Additionally, an association between thymoma-associated myasthenia gravis and decreased miR-376a/miR-376c expression was found. Autoimmune regulation is known to be downregulated in thymoma-associated myasthenia gravis, and in thymus cells with downregulated autoimmune regulation there was simultaneous downregulation in miR-376a, miR-376c, and miRNA-12a-5p expression.
In early-onset myasthenia gravis patients, 61 miRNA's were found to be either significantly downregulated or upregulated. The most downregulated miRNA was found to be miR-7-5p, whose target gene is CCL21. CCL21 is known to aberrantly recruit B-cells in the thymus of early-onset myasthenia gravis patients, and was found to be highly expressed in early-onset myasthenia gravis patients, potentially explaining the abnormally large amounts of B cells found in thymic hyperplasia.
Aside from miRNA's corresponding to altered thymus function, there are other several key miRNA's that are correlated with myasthenia gravis. MiR-15 cluster (miR-15a, miR-15b, and miR-15c) was shown to be associated with autoimmunity, in that its downregulation increased CXCL10 expression, a target gene involved in T-cell signaling. CXCL10 expression was also shown to be increased in the thymus of myasthenia gravis patients. Additionally, miR-146 was found to be upregulated in myasthenia gravis patients. In these patients with upregulated miR-146, there was a concurrent increase in proteins that correspond to a wide array of immune responses, specifically TLR4, CD40, and CD80.
DNA Methylation
DNA methylation is the epigenetic process by which methyl groups are added to either adenine or cytosine bases, which results in the repression of that sequence when cytosine methylation occurs. DNA methylation was found to be a factor in increasing the likelihood of acquiring myasthenia gravis, albeit this topic has not been widely researched. Research in China has identified the gene CTLA-4 (cytotoxic T lymphocyte antigen-4) as being highly methylated in myasthenia gravis patients compared to control groups throughout the entire span of the disease. The CTLA-4 gene produces an antigen of the same name that is presented on killer T-cells and allows for the suppression of the immune response. Methylation of this gene represses production of the antigen CTLA-4—a pattern seen in a significant majority of myasthenia gravis patients—and can explain the elevated immune response seen in myasthenia gravis. Furthermore, myasthenia gravis patients with thymic abnormalities (approximately 10-20% of all myasthenia gravis patients) had even higher levels of CTLA-4 methylation than other myasthenia gravis patients. It is not extensively researched why certain genes are hypermethylated in these cases, but information on myasthenia gravis largely points to upregulation of the DNA methyltransferase genes DNMT1, DNMT3A, and DNMT3B in patients with myasthenia gravis.
In addition to CTLA-4 methylation, hypermethylation of the growth hormone secretagogue receptor gene was seen in patients with thymoma-associated late-onset myasthenia gravis.
Growth hormone secretagogue receptor hypermethylation is detected in a wide variety of cancers, however only recently has been correlated with the development of thymoma-associated myasthenia gravis. Although it is seen in approximately 1/4 of thymoma-associated myasthenia gravis subjects, it is not a reliable biomarker for the disease, and its relevance to disease progression is not well known.
Long ncRNA
Long ncRNA (lncRNA) are a second type of non-coding RNA that are key post-transcriptional modifiers of protein-coding gene expression. These also play a significant role in myasthenia gravis. Their aberrant regulation can cause differential expression in downstream genes. For instance, the differential expression of lncRNA interferon gamma antisense RNA negatively regulates the expression of HLA-DRB and HLA-DOB,
two genes implicated in the body's autoimmune response by differentiating endogenous and foreign proteins. As seen in myasthenia gravis patients with downregulated lethal (let)-7 lncRNA, it was also found that the level of let-7 lncRNA was negatively correlated with levels of interleukin (IL)-10, a gene responsible for inhibiting cytokine secretion/activation, antigen presentation, and macrophage activity, but also for exhibiting anti-tumor effects. Therefore, the negative correlation between let-7 lncRNA and IL-10 levels and its specific effects on myasthenia gravis development are ambiguous.
In addition to aberrant regulation of downstream target genes, lncRNA also affect expression by acting as competing endogenous RNA (ceRNA). The competing endogenous RNA theory states that transcripts sharing common miRNA binding sites can compete to bind these identical miRNAs, and in this way lncRNAs can bind miRNAs, regulating their downstream binding activity and affecting their function. In the case of myasthenia gravis, the lncRNA small nucleolar RNA host gene (SNHG) 16 regulates the expression of IL-10 by adsorbing let-7c-5p, a miRNA that commonly associates with IL-10, as a competing endogenous RNA.
Epigenetic Treatments
Diagnosis of myasthenia gravis, individual prognosis, and the level of treatment needed can be determined by detecting the amounts of circulating miRNA.
Immunosuppressants represent a large category in clinical studies for myasthenia gravis treatment, as they reduce the hyperactive immunological response in T-cells presenting acetylcholine receptor-binding antigens.
By overexpressing miR-146, studies show that patients with early-onset myasthenia gravis can have antigen-specific suppressive effects. This has implications in reducing the immune response of myasthenia gravis patients and improving prognosis. Likewise, miR-155 is proven to be correlated with myasthenia gravis-associated thymic inflammation and immune response. Research is being conducted whereas repression of miR-155 could reduce these aberrant effects.
Lastly, the miRNA's miR-150-5p and miR-21-5p are consistently shown to be elevated in myasthenia gravis patients with acetylcholinergic receptor antibodies (in contrast to the MuSK-binding variant of myasthenia gravis), therefore these two miRNA's are reliable biomarkers in detecting this variant of myasthenia gravis.
Neurodegenerative diseases of the central nervous system
Alzheimer's Disease (AD)
Alzheimer's disease (AD) is the most prevalent form of dementia among the elderly. The disease is characterized behaviorally by chronic and progressive decline in cognitive function, beginning with short-term memory loss, and neurologically by buildup of misfolded
tau protein
The tau proteins (abbreviated from tubulin associated unit) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintaining ...
and associated
neurofibrillary tangles
Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is k ...
, and by amyloid-beta senile plaques
amyloid-beta senile plaques. Several genetic factors have been identified as contributing to AD, including mutations to the
''amyloid precursor protein'' (''APP'') and
''presenilins 1 and 2'' genes, and familial inheritance of ''
apolipoprotein E
Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease.
APOE belongs to a family of fat-binding proteins called apolipoproteins. ...
'' allele epsilon 4. In addition to these common factors, there are a number of other genes that have shown altered expression in Alzheimer's disease, some of which are associated with epigenetic factors.
Epigenetic factors
250 px, Brain-derived neurotrophic factor
;ncRNA: ncRNA that is encoded antisense from an intron within the beta-amyloid cleaving enzyme gene,
''BACE1,'' is involved in AD.
This ncRNA, ''
BACE1-AS
''BACE1-AS'', also known as BACE1 antisense RNA ( non-protein coding), is a human gene at 11q23.3 encoding a long noncoding RNA molecule. It is transcribed from the opposite strand to ''BACE1'' and is upregulated in patients with Alzheimer's dis ...
'' (for antisense), which overlaps exon 6 of ''BACE1'', is involved in increasing the stability of the ''BACE1'' mRNA transcript. As that gene's name suggests, BACE1 is an enzymatic protein that cleaves the Amyloid Precursor Protein into the insoluble amyloid beta form, which then aggregates into senile plaques. With increased stability of ''BACE1'' mRNA resulting from ''BACE1-AS'', more ''BACE1'' mRNA is available for translation into BACE1 protein.
;miRNA: factors have not consistently been shown to play a role in progression of AD. miRNAs are involved in post-transcriptional gene silencing via inhibiting translation or involvement in
RNAi
RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by o ...
pathways. Some studies have shown upregulation of miRNA-146a, which differentially regulates neuroimmune-related Interleukin-1R associated kinases IRAK1 and IRAK2 expression, in human AD brain, while other studies have shown upregulation or downregulation of miRNA-9 in brain.
;DNA methylation: In Alzheimer's disease cases, global DNA hypomethylation and gene-specific hypermethylation has been observed, though findings have varied between studies, especially in studies of human brains. Hypothetically, global hypomethylation should be associated with global increases in transcription, since CpG islands are most prevalent in gene promoters; gene-specific hypermethylation, however, would indicate that these hypermethylated genes are repressed by the methylation marks. Generally, repressive hypermethylation of genes related to learning and memory has been observed in conjunction with derepressive hypomethylation of neuroinflammatory genes and genes related to pathological expression of Alzheimer's disease. Reduced methylation has been found in the long-term memory-associated temporal neocortex neurons in monozygotic twins with Alzheimer's disease compared to the healthy twin.
Global hypomethylation of CpG dinucleotides has also been observed in hippocampus
and in entorhinal cortex layer II
of human AD patients, both of which are susceptible to AD pathology. These results, found by probing with immunoassays, have been challenged by studies that interrogate DNA sequence by
bisulfite sequencing
Bisulfite sequencing (also known as bisulphite sequencing) is the use of bisulfite treatment of DNA before routine sequencing to determine the pattern of methylation. DNA methylation was the first discovered epigenetic mark, and remains the mo ...
, a CpG transformation technique which is sensitive to CpG methylation status, in which global hypomethylation has been observed.
;COX-2: At the individual gene level, hypomethylation and thus derepression of
''COX-2'' occurs, inhibition of which reduces inflammation and pain, and hypermethylation of
''BDNF'', a neurotrophic factor important for long-term memory.
Expression of ''
CREB
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
'', an activity-dependent transcription factor involved in regulating ''BDNF'' among many other genes, has also been shown to be hypermethylated, and thus repressed, in AD brains, further reducing ''BDNF'' transcription.
Furthermore,
synaptophysin (''SYP''), the major synaptic vesicle protein-encoding gene, has been shown to be hypermethylated and thus repressed, and transcription factor ''
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
'', which is involved in immune signaling, has been shown to be hypomethylated and thus derepressed.
Taken together, these results have elucidated a role for dysregulation of genes involved in learning and memory and synaptic transmission, as well as with immune response.
;Hypomethylation: has been observed in promoters of ''presenilin 1'',
''GSK3beta'', which phosphorylates tau protein,
and ''BACE1'',
an enzyme that cleaves APP into the amyloid-beta form, which in turn aggregates into insoluble senile plaques. Repressive hypermethylation caused by amyloid-beta has been observed at the promoter of ''NEP'', the gene for neprilysin, which is the major amyloid-beta clearing enzyme in the brain.
This repression of NEP could result in a feed-forward buildup of senile plaques; combined with the observed increase in AD brains of ''BACE1-AS'' and corresponding increases in BACE1 protein and amyloid beta,
multiple levels of epigenetic regulation may be involved in controlling amyloid-beta formation, clearance or aggregation, and senile plaque deposition. There may be some effect of age in levels of DNA methylation at specific gene promoters, as one study found greater levels of methylation at ''APP'' promoters in AD patients up to 70 years old, but lower levels of methylation in patients greater than 70 years old.
Studies on differential DNA methylation in human AD brains remain largely inconclusive possibly owing to the high degree of variability between individuals and to the numerous combinations of factors that may lead to AD.
;Histone marks: Acetylation of lysine residues on histone tails is typically associated with transcriptional activation, whereas deacetylation is associated with transcriptional repression. There are few studies investigating specific histone marks in AD. These studies have elucidated a decrease in acetylation of lysines 18 and 23 on N-terminal tails of histone 3 (H3K18 and H3K23, respectively)
and increases in HDAC2 in AD brains
- both marks related to transcriptional repression. Age-related cognitive decline has been associated with deregulation of H4K12 acetylation, a cognitive effect that was restored in mice by induction of this mark.
Treatments
Treatment for prevention or management of Alzheimer's disease has proven troublesome since the disease is chronic and progressive, and many epigenetic drugs act globally and not in a gene-specific manner. As with other potential treatments to
prevent
Prevention may refer to:
Health and medicine
* Preventive healthcare, measures to prevent diseases or injuries rather than curing them or treating their symptoms
General safety
* Crime prevention, the attempt to reduce deter crime and crimin ...
or
ameliorate symptoms of AD, these therapies do not work to cure, but only ameliorate symptoms of the disease temporarily, underscoring the chronic, progressive nature of AD, and the variability of methylation in AD brains.
;Folate and other B vitamins: B vitamins are involved in the metabolic pathway that leads to SAM production. SAM is the donor of the methyl group utilized by DNA methyltransferases (DNMTs) to methylate CpGs. Using animal models, Fuso et al. have demonstrated restoration of methylation at previously hypomethylated promoters of ''presenilin 1'', ''BACE1'' and ''APP''
- a hypothetically stable epigenetic modification that should repress those genes and slow the progression of AD. Dietary SAM supplementation has also been shown to reduce oxidative stress and delay buildup of neurological hallmarks of AD such as amyloid beta and phosphorylated tau protein in transgenic AD mice.
;AZA: Khan and colleagues have demonstrated a potential role for
neuroglobin
Neuroglobin is a member of the vertebrate globin family involved in cellular oxygen homeostasis and reactive oxygen/nitrogen scavenging. It is an intracellular hemoprotein expressed in the central and peripheral nervous system, cerebrospinal fluid ...
in attenuating amyloid-related neurotoxicity.
5-aza-2' deoxycitidine (AZA, or decitabine), a DNMT inhibitor, has shown some evidence for regulating neuroglobin expression, though this finding has not been tested in AD models.
;Histone-directed treatments: Though studies of histone marks in AD brains are few in number, several studies have looked at the effects of HDACis in treatment of Alzheimer's disease. Class I and II HDAC inhibitors such as trichostatin A, vorinostat, and sodium butyrate, and Class III HDACis, such as nicotinamide, have been effective at treating symptoms in animal models of AD. While promising as a therapeutic in animal models, studies on the long-term efficacy of HDACis and human trials have yet to be conducted.
;Sodium butyrate: Sodium butyrate is a class I and II HDACi and has been shown to recover learning and memory after 4 weeks,
decrease phosphorylated tau protein, and restore dendritic spine density in the hippocampus of AD transgenic mice.
Histone acetylation resulting from diffuse sodium butyrate application is especially prevalent in the hippocampus, and genes involved in learning and memory showed increased acetylation in AD mice treated with this drug.
;Trichostatin A: Trichostatin A is also a class I and II HDACi that rescues fear learning in a fear conditioning paradigm in transgenic AD mice to wild type levels via acetylation on histone 4 lysine tails.
;Vorinostat: Vorinostat is a class I and II HDACi that has been shown to be especially effective at inhibiting HDAC2 and restoring memory functions in non-AD models of learning deficits.
One study showed vorinostat is effective at reversing contextual memory deficits in transgenic AD mice.
Huntington's (HD)
![Striatum Structural MRI](https://upload.wikimedia.org/wikipedia/commons/7/7d/Striatum_Structural_MRI.png)
Huntington's disease (HD) is an inherited disorder that causes progressive degeneration of neurons within the
cerebral cortex
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...
and
striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
of the brain
resulting in loss of motor functions (involuntary muscle contractions), decline in cognitive ability (eventually resulting in dementia), and changes in behavior.
Genetics and underlying causes
Huntington's is caused by an autosomal dominant mutation expanding the number of glutamine codon repeats (CAG) within the
Huntingtin
Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role and also for ...
gene (Htt).
The Htt gene encodes for the huntingtin protein which plays a role in normal development but its exact function remains unknown.
The length of this CAG repeat correlates with the age-of-onset of the disease. The average person without Huntington's has less than 36 CAG repeats present within the Htt gene. When this repeat length exceeds 36, the onset of neuronal degradation and the physical symptoms of Huntington's can range from as early as 5 years of age (CAG repeat > 70) to as late as 80 years of age (CAG repeat < 39).
This CAG expansion results in mRNA downregulation of specific genes, decreased histone acetylation, and increased histone methylation.
The exact mechanism of how this repeat causes gene dysregulation is unknown, but epigenome modification may play a role. For early-onset Huntington's (ages 5–15), both transgenic mice and mouse striatal cell lines show brain specific histone H3 hypoacetylation and decreased histone association at specific downregulated genes within the striatum (namely Bdnf, Cnr1, Drd2 - dopamine 2 receptor, and Penk1 - preproenkephalin).
For both late- and early-onset Huntington's, the H3 and H4 core histones associated with these downregulated genes in Htt mutants have hypoacetylation (decreased acetylation) compared to wild-type Htt.
This hypoacetylation is sufficient to cause tighter chromatin packing and mRNA downregulation.
Along with H3 hypoacetylation, both human patients and mice with the mutant Htt have increased levels of histone H3 lysine 9 trimethylation.
This increase in H3-K9 trimethylation is linked to an increased expression of the methyltransferase ESET/SETDB1 (ERG-associated protein with SET domain (ESET)), which targets and trimethylates H3-K9 residues.
It is proposed that this hypermethylation may account for the onset of specific gene repression in Htt mutants.
HDAC inhibitors
Huntington patients and both mouse and Drosophila models show histone H3 and H4 hypoacetylation. There are currently no treatments for the disease but numerous HDAC inhibitors have been tested and shown to reverse the certain symptoms caused by the Htt mutation.
Parkinson's Disease (PD)
![Lewy Koerperchen](https://upload.wikimedia.org/wikipedia/commons/3/32/Lewy_Koerperchen.JPG)
Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra by causes unknown. Several genes and environmental factors (e.g. pesticide exposure) may play a role in onset of PD. Hallmarks include mutations to the alpha-synuclein gene,
''SNCA'', as well as ''PARK2'', ''PINK1'', ''UCHL1'', ''DJ1'', and ''LRRK2'' genes, and fibrillar accumulation of
Lewy bodies
Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias ( Parkinson's disease dementia and dementia with Lewy bodies (DLB)), and ...
from misfolded alpha-synuclein. Symptoms are most noticeably manifested in disorders of movement, including shaking, rigidity, deficits in making controlled movements, and slow and difficult walking. The late stages of the disease result in dementia and depression. Levodopa and dopaminergic therapy may ameliorate symptoms, though there is no treatment to halt progression of the disease.
Epigenetic factors
;ncRNA: Reductions of miR-133b correlated to decreased numbers of dopaminergic neurons in the midbrain of PD patients.
miR-132, meanwhile, is negatively correlated with dopaminergic neuron differentiation in the midbrain.
miR-7 and miR-153 act to reduce alpha-synuclein levels (a hallmark of PD) but are reduced in PD brain.
;DNA methylation: Neurons of PD patients show hypomethylation of ''tumor necrosis factor (TNF) alpha'' encoding sequence, overexpression of which leads to apoptosis of neurons.
Cerebrospinal fluid of PD patients also shows elevated TNF alpha.
Research indicates there may be a link between DNA methylation and SNCA expression.
Furthermore, human and mouse models have shown reduction of nuclear DNMT1 levels in PD subjects, resulting in hypomethylated states associated with transcriptional repression.
;Histone marks: alpha-synuclein, the protein encoded by ''SNCA'', can associate with histones and prevent their acetylation in concert with the HDACs HDAC1 and Sirt2.
Furthermore, it has been demonstrated that alpha-synuclein binds histone 3 and inhibits its acetylation in ''Drosophila''.
Dopamine depletion in Parkinson's disease is associated with repressive histone modifications, including reduced H3K4me3, and lower levels of H3 and H4 lysine acetylation after levodopa therapy (a common treatment of PD).
Treatments
Epigenetic treatments tested in models of PD are few, though some promising research has been conducted. Most treatments investigated thus far are directed at histone modifications and analysis of their roles in mediating alpha-synuclein expression and activity. Pesticides and paraquat increase histone acetylation, producing neurotoxic effects similar to those seen in PD, such as apoptosis of dopaminergic cells.
Despite this, treatment with HDACis
seems to have a neuroprotective effect.
Multiple Sclerosis
Multiple Sclerosis (MS) is a demyelinating neurodegenerative disease that does not have a confirmed cause, but is widely considered to be an autoimmune disease in nature. It is indicated by demyelination of the nerves of the brain and spinal cord. Its symptoms are unique in nature and vary, but include those that have degenerative effects in the eyes and limbs. These can present themselves as numbness or atrophy, shock like sensations, paralysis, as well as lack of coordination or tremors, within the extremities. Within the eye, multiple sclerosis can cause blurriness, double vision, pain, or vision loss. Multiple sclerosis effects can be presented throughout other realms of the body, but is largely characterized by these main symptoms. Some of these can include loss of sexual or excretory function and epilepsy. While there are a few subcategories of multiple sclerosis, in most instances, the disease afflicts in a relapsing nature, where relapses of symptoms might not occur for extended periods of time, yielding more to the uncertainty of the disease. There is no known cure for MS, but measures can be taken post relapse to regain loss of function and the symptoms can be mitigated via therapeutic or medicinal means.
Epigenetic Factors
Because of the outside factors that precede multiple sclerosis and the heritability typically occurring within the mother, it is thought to have an epigenetic cause. Some factors that may increase the incidence of MS are smoking, vitamin deficiency, and a history of some viral infections—which are factors that can induce epigenetic change.
=Human Leukocyte Antigen-DRB1*15 Allele
=
Human leukocyte antigen-DRB1*15 haplotype is a potential risk factor of MS. Because of the increased likelihood of the mother's human leukocyte antigen-DRB1*15 allele being passed onto their children, this contributes to the instances of MS being more prevalent from the mother. HLA-DRB1 is thought to be regulated via epigenetic means. The correlation of MS and this allele is speculated to be due to the presence of hypomethylation in the CpG island of HLA-DRB1, and those that carry the allele tend to exhibit this hypomethylation. HLA-DRB1 exon 2 is a particular region where evidence has shown that methylation is shown to be important in regulation. Research has furthered the evidence that variation in HLA-DRB1 DMR, which is a mechanism that is methylation regulated, that in turn regulates increased HLA-DRB1 expression, displays an increased risk for MS, and the exhibition of the disease.
=miRNA
=
Higher levels of expression of specific types of miRNA are often seen in the brain of those afflicted, showing an association of these types of miRNA and MS. Higher expression of miR-155 and miR-326 is often associated with CD4+T cell differentiation, and with this differentiation, instances of autoimmune encephalitis occur, which is the link with which it is thought that smoking can induce epigenetic changes that increase susceptibility to MS. Higher expression levels of miR-18b, miR-493, miR-599, and miR-96 are often seen in patients diagnosed with MS. miR-145 detection appears to be a promising future diagnostic tool due to its high specificity of 90% and sensitivity of 89.5% in whole blood testing due to its capability of distinguishing healthy patients versus those with MS. A symptom associated with MS patients is white matter lesions in the brain, and these lesions when biopsied showed higher expression of miR-155, miR-326 and miR-34a. These are especially notable due to the fact that overexpression of these miRNA's cause downregulation of CD47, leading to myelin phagocytosis, because of CD47's role of inhibiting macrophage activity.
=DNA Methylation
=
MS patients can be identified through observation of abnormal DNA methylation patterns in genes responsible for inflammation and myelination factor expression. Methylation occurs in the genomic region, CpG island, and is imperative in regulation of transcription. A methylated CpG region typically is the mechanism that will silence a gene, whereas a hypomethylated region is able to induce transcription. Using methylation inhibitors it has been shown that allowing higher proliferation of T cells can be achieved by preventing silencing. Abnormalities in methylation patterns increase the generation of CD4+T auto reactive. Hypomethylation of CpG regions of the PAD2 gene, a regulator of MBP which in turn regulates myelin, is also associated with higher instances of MS. This hypomethylation leads to overexpression of the PAD2 gene. These patterns have been observed in the white matter of patients with MS. While methylation is an indicator of MS, its effects are more specialized to location in MS, for example, where these patterns are observed in white matter.
=Histone Modifications
=
Association of abnormal histone modification in MS patients can be found in lesions located in the brain, with most instances of this being observed in patients over time and in lesions located in the frontal lobe. Higher instance of histone acetylation can be seen in patients afflicted over time, but this is counteracted by lower instances of histone acetylation in lesions found on the brain early in the course of the disease. The mechanisms by which histone modifications work in the progression of MS are unconfirmed, but changes in acetylation are often associated with the disease.
=Treatments
=
HDAC Inhibitors
Trichostatin
Positive responses were observed in animal trials utilizing this HDAC inhibitor, associated with mediation of inflammatory pathways and thus resulting in lower instances of inflammatory responses in the brain. It was also shown to be effective in decreasing levels of disability when the mice were in a relapsing stage of MS. Trichostatin's mediation of symptoms is not well known but is thought to work in increasing acetylation at the H3 and H4 histones in CD4+T cells where MS patients often display differences in acetylation levels at these histones that control patients do not.
Vorinostat
Animal trials were utilized along with the testing of human myeloid dendritic cells. Not much is known about the mechanisms of Vorinostat, however regulation of Th1/Th17 cytokine expression, which are responsible for inducing inflammation, were observed, thereby decreasing instances of inflammation and demyelination. Decreased patterns of T cell proliferation were also observed, similar to how Trichostatin mediates disease symptoms.
Valpropic Acid
Valpropic acid has been shown to have positive results in animal trials, in the mitigation of the disease by regulating the severity and duration of MS. Its mechanism is decreasing the presentation of miRNA. Its mechanism for such has been observed in rats by shifting Th1 and Th17 to Th2 (responsible for inducing inflammation), thereby downregulating miRNA expression in inflammatory cytokines, tumor mediating mechanisms, and the spine. This is another instance in which T cell expression regulation is present, by preventing proliferation through interference of its pathway, similar to Trichostatin and Vorinostat. Another effect of VPA is its prevention of macrophage and lymphocyte proliferation in the spinal cords of MS rats. Currently, no HDAC inhibitors are in use for the mitigation of symptoms in MS patients however, some are in pre-clinical trials at this time.
See also
*
Neuromuscular disease
A neuromuscular disease is any disease affecting the peripheral nervous system (PNS), the neuromuscular junction, or skeletal muscle, all of which are components of the motor unit. Damage to any of these structures can cause muscle atrophy and w ...
References
{{Medicine
Epigenetics