Republic of Iraq

Ministry of Higher Education

and Scientific Research

Al-Nahrain University

College of Biotechnology

Molecular genetic

Gene-by-environment interactions in
Alzheimer’s disease and Parkinson’s disease

By:
Naba Fuad Salim

Supervisor :
Dr. Ibrahim Ahmed
2020
Abstract
Diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) arise from
complex interactions of genetic and environmental factors, with genetic variants
regulating individual responses to environmental exposures (i.e. gene-by-environment
interactions). Identifying gene-by-environment interactions will be critical to fully
understanding disease mechanisms and developing personalized therapeutics, though
these interactions are still poorly understood and largely under-studied. Candidate gene
approaches have shown that known disease risk variants often regulate response to
environmental factors. However, recent improvements in exposome- and genome-wide
association and interaction studies in humans and mice are enabling discovery of novel
genetic variants and pathways that predict response to a variety of environmental factors.
Here, we highlight recent approaches and ongoing developments in human and rodent
studies to identify genetic modulators of environmental factors using AD and PD as
exemplars. Identifying gene-by-environment interactions in disease will be critical to
developing personalized intervention strategies and will pave the way for precision
medicine.
 Index

1.0. Introduction
1.1Role of epigenetics in Alzheimer’s and Parkinson’s disease
1.2.Two common causes of neurodegeneration
1.2.1. Alzheimer’s disease
1.2.2. Parkinson’s disease

1.3. Role of AD & PD susceptibility genes

1.4.Therapeutics for neurodegenerative diseases based on targeting
molecules involved in epigenetic modification
1.5.Pan-epigenetic modifiers are potential treatments for
neurodegenerative disorders
1.6. DNA methylation occurs at specific CpG sites & can be modulated
by surrounding genetic polymorphisms in an allele-specific manner
1.7.Environmental factors result in epigenetic modification of key
neurodegenerative genes
1.8.Susceptibility genes
2.1Environmental factors & epigenetic modification in
neurodegeneration
2.2 Global epigenetic changes occur at a genotypic level

2.3 Aβ Homeostasis as a Target of Environmental Factors

2.4 Tau Hyperphosphorylation by Environmental Factors

2.5 Early Exposure to Environmental Factors and AD or PD

Development: Epigenetic Evidence

3.0 References
1.0. Introduction
1.1Role of epigenetics in Alzheimer’s and Parkinson’s disease

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are two common
neurodegenerative diseases that result in the progressive damage or death of neurons.
Environmental agents have the potential to damage the developing and mature
nervous system, resulting in neurodegenerative diseases. Heritable changes in gene
expression that do not involve coding sequence modifications are referred to as
‘epigenetic’. These modifications include DNA methylation and downstream
modification of histones. Environmental factors, including heavy metals and dietary
folate intake, perturb neurodegenerative genes by epigenetic means, leading to
altered gene expression and late-onset neurodegenerative diseases. Research into the
genetic control of DNA methylation indicates an allelic skewing in a significant
proportion of genes. This phenomenon may determine how an individual’s genetic
makeup can alter the effect an environmental factor has on their risk of developing
neurodegeneration. Finally, preliminary evidence using cell culture and transgenic
animal models suggests that whole classes of pan-epigenetic modifiers will have
significant protective effects against common neurodegenerative diseases.
 1.2.Two common causes of neurodegeneration
Neurodegenerative diseases result in the progressive damage or death of neurons,
leading to a gradual deterioration of the bodily functions controlled by the affected
part of the nervous system. Alzheimer’s disease (AD) is the most common cause of
neurodegeneration. There are other forms of neurodegeneration that differ in clinical
symptoms and neuropathology but share some common genetic etiology, including
Parkinson’s disease (PD) and the frontotemporal dementias. Environmental agents
have the potential to damage the developing and mature nervous system, resulting in
neurodegenerative diseases. Heritable changes in gene expression that do not involve
coding sequence modifications are referred to as ‘epigenetic’. It has been hypothesized
that environmental factors can perturb gene regulation by epigenetic modification,
leading to late-onset neurodegenerative diseases.

1.2.1. Alzheimer’s disease

Alzheimer’s disease (OMIM 104300 is the most common progressive

neurodegenerative disorder, affecting approximately 13% of the population at 80 years
of age.AD is typified clinically by initial memory deficits and progressive loss of higher
cognitive function. However, AD is diagnosed definitively by two key
neuropathological features: senile plaques and neurofibrillary tangles. Senile plaques in
the extracellular spaces between neurons are spherical deposits that consist of central
cores of amyloid β (Aβ) fibrils, surrounded by degenerated neurites and glial cells.

1.2.2. Parkinson’s disease

Parkinson’s disease (OMIM 168600 is the second most common progressive

neurodegenerative disorder, affecting approximately 2% of the population who are aged
65 years The disease is characterized clinically by a combination of motor symptoms
including tremor, bradykinesia and rigidity Neuropathologically, the disease is
characterized by severe loss of dopaminergic neurons in the substantia nigraand
cytoplasmic inclusions of insoluble protein aggregates known as Lewy bodies The
main component of Lewy bodies is α-synuclein .
1.3. Role of AD & PD susceptibility genes

Several hundreds of association studies have been published in recent years claiming or
refuting association between variants in candidate genes and the risk of AD or PD.
However, results published so far are often conflicting and inconclusive, reflecting
genetic heterogeneity of the studied populations and inadequate sample size. One of the
most replicated susceptibility locus for AD is the APOE gene. Inheritance of two copies
of the ApoE ε4 allele increases the risk of developing late-onset AD by approximately
15-fold compared with the ApoE ε3 allele The ApoE ε4 allele is associated with higher
plasma cholesterol levels, and elevated Aβ deposition An online summary of all the
reported susceptibility loci for AD is available .

Two genes have been consistently associated with PD. A polymorphic dinucleotide
repeat sequence in the SNCA promoter affects gene transcription and has been associated
with increased risk of PD . The MAPT gene codes for a molecule that stabilizes tubulin
cytoskeletal structures and plays an important role in axonal transport Mutations
in MAPT that alter the ratio of the two MAPT isoforms give rise to frontotemporal
dementia but have not been demonstrated to be causative for AD or PD. Nonetheless,
utilizing a set of polymorphisms that differentiate the MAPT haplotypes H1 and H2 ,
meta-analyses of association studies have demonstrated a significant effect of MAPT on
late-onset AD and PD disease risk. The inheritance of the H1 haplotype is associated
with increased expression of MAPT A genome-wide association study utilizing one of the
largest PD cohorts confirmed the role of MAPT and SNCA as susceptibility genes ]. An
online summary of all the reported susceptibility loci for PD is available.

A major confounding factor in the discovery of susceptibility genes has recently

gained attention, namely epistasis or gene–gene interactions, in which the actions of
two or more genes determine disease phenotype. We have identified a crucial gene–
gene interaction between the GSK3β gene, which encodes a serine/threonine kinase
implicated in regulation of numerous physiological responses by phosphorylating a
variety of nuclear and cytoplasmic proteins, and the MAPT gene in both AD and
PD which has now been replicated in independent laboratories .
 1.4.Therapeutics for neurodegenerative diseases based on targeting
molecules involved in epigenetic modification

Therapeutic developments for neurodegeneration have focused on the two main areas of
epigenetic modifications. DNA methylation is a reversible process that is catalyzed by
DNA DNMT. The downstream acetylation and deacetylation of histones as a result of site-
specific DNA methylation are catalyzed by histone acetyltransferase and histone
deacetylases (HDACs), respectively . Similarly, histone methyltransferases and histone
demethylases regulate histone methylation .

In vitro models of HDAC inhibition-mediated neuroprotection have identified a number

of protective genes and pathways, including cell cycle protein p21 the actin-binding
gelsolin, and the molecular chaperone HSP70 . Pan-HDAC inhibitors had beneficial
effects in models for spinal muscle atrophy, a degenerative disease that affects motor
neurons. Spinal muscle atrophy is typically accompanied by downregulation of
the SMN1 and SMN2 genes. Treatment with HDAC reverses the hypermethylation and
downregulation of the SMN2 gene promoter in vitro and thus could be used to
raise SMN2 gene expression to normal physiological levels in spinal muscle atrophy
patients .

An important concept in neurodegenerative disorders, such as AD and PD, is the idea that
neuropathological intraneuronal aggregates interfere with transcription and cause deficits
in synaptic plasticity and cognition Tsai et al. demonstrated that HDAC inhibitors restored
histone acetylation status, learning and memory in a mouse model of neurodegeneration, in
which p25, another cell cycle protein implicated in neurodegenerative disease, was
overexpressed. Of interest, the effects of HDAC inhibitors could also be mimicked by
increasing the environmental enrichment of the cages, such as a supply of coloured toys, in
which the p25 transgenic mice are housed . Recent studies indicate that HDAC inhibitors
may represent a promising therapeutic strategy for PD as well. Administration of HDAC
inhibitors in vivo or in vitro rescued α-synuclein-induced toxicity.

Several drugs targeting DNA methylation and histone deacetylation enzymes have
already been approved for the treatment of certain tumors and others are in clinical trials.
The first DNA methylation inhibitor (Vidaza®) was approved in 2004 by the US FDA for
use in human subjects to treat myelodysplastic syndromes In addition, the HDAC
inhibitor SAHA (Vorinostat) is prescribed to treat cutaneous T-cell lymphoma and is
currently being tested in Phase III trials for other cancers These molecules are obvious
candidates for novel therapeutic strategies for neurodegenerative disorders. Finally, it
should be noted that the HDAC inhibitors only alter a small number of genes (<10% of the
genome) as demonstrated by genome-wide transcript profiling by microarrays Moreover,
each HDAC inhibitor is associated with a specific ‘genetic signature’, or the subset of
genes whose expression are altered by these chemicals Thus, although neurodegeneration-
associated genes such as APP and PSEN1 appear to be hypomethylated in the disease
state specific HDAC inhibitors, such as the compound 106, could be used to increase the
expression of neuroprotective genes without altering the level of pathogenic genes, such
as APP.
1.5.Pan-epigenetic modifiers are potential treatments for neurodegenerative
disorders

▪ Histone deacetylase inhibitors appear to modify the epigenetic signature of a panel of

neuroprotective genes.

▪ Current US FDA-approved inhibitors are obvious candidates for the treatment of

neurodegenerative diseases.

1.6. DNA methylation occurs at specific CpG sites & can be modulated by
surrounding genetic polymorphisms in an allele-specific manner

▪ Analysis of global methylation using large-scale genotyping and DNA methylation

arrays have identified a large number of genes that display allelic skewing in their
methylation profile.

▪ Environmental factors, such as smoking, alter DNA methylation in an allele-dependent

manner.

1.7.Environmental factors result in epigenetic modification of key

neurodegenerative genes

▪ Exposure to lead during development in animal models leads to hypomethylation of

the APP gene and increased Aβ peptide production.

▪ Folate-deficient diet in mouse models lead to hypomethylation and dysregulation of

expression of APP, PSEN1 and BACE.

1.8.Susceptibility genes

▪ Gene–gene (epistasis) and gene–environment factors are potential confounders for the
association between candidate susceptibility genes and risk of neurodegenerative diseases.

▪ The only consistently demonstrated susceptibility gene is the APOE gene for late-onset
AD.
2.1Environmental factors & epigenetic modification in neurodegeneration

Environmental agents have the potential to damage the developing and mature nervous
system, resulting in neurodegenerative diseases,. In addition to genetic risk factors for
neurodegenerative disease, other contributive factors include gender, levels of education,
inflammation, stroke, smoking, head trauma, infection, vitamin deficiencies and diet, and
chemical exposur. The genotype at a particular locus may account for an individual’s
susceptibility to develop a disease, especially after the exposure to endogenous and
exogenous agents, defined as gene–environment interaction. Few environmental risk factors
have been identified for AD although an important role for diet and educational levels in the
pathogenesis of the disease is suggested by several studies On the other hand, multiple
environmental factors have been consistently associated with an increased risk for PD .
Numerous studies support the hypothesis that environmental factors, including heavy metals
and dietary factors, could perturb gene regulation in a long-term fashion by epigenetic
modification, leading to late-onset neurodegenerative diseases

2.1.1▪ Exposure to heavy metals

Recent studies in rodents have demonstrated that exposure to the xenobiotic metal lead
(Pb) during brain development predetermined the expression and regulation of the APP and
its amyloidogenic Aβ product in old age . Wu et al. demonstrated that the expression of
AD-related genes (APP and PSEN1) as well as their transcriptional regulator (SP1) were
elevated in aged monkeys exposed to Pb as infants . Basha et al. also reported that
developmental exposure of rats to Pb resulted in an early transient and a delayed
overexpression (20 months later) of APP and its amyloidogenic Aβ product by inhibiting
DNMTs and thus hypomethylating promoters of genes associated with AD

2.1.2▪ Diet
Dietary components can modulate both the genome and the epigenome and potentially
modify the risk and/or severity of a variety of disease conditions, including
neurodegenerative ones A prospective study of dietary patterns and risk of PD suggests that
diets with high intakes of fruit, vegetables, whole grains, fish and poultry, a moderate intake
of alcohol and a low intake of saturated fats were protective against PD Vitamin B12 is
naturally found in leafy greens such as spinach and turnip greens, and some fruits and
vegetables are rich food sources of folate . Folate and vitamin B12 are essential cofactors
for the methionine/homocysteine cycle, also known as the one-carbon metabolism pathway,
in the brain .

2.1.3▪ Pesticide exposure & oxidative stress

The most characterized model for environmental insults in PD research is the free radical
injury induced by exposure to MPTP. A metabolite of MPTP (MPP +) is selectively taken up
by dopaminergic terminals and concentrated in neuronal mitochondria in the substantia
nigra. MPP+ binds to and inhibits complex I of the mitochondrial electron transport chain,
thereby producing the same oxidative stress as detected in PD patients .
2.2▪ Global epigenetic changes occur at a genotypic level
Several important advances in the understanding of epigenetic modification and the
regulation of gene expression across the genome have been made that will be key in the
understanding of how to interpret epigenetic data in relation to disease process. It has been
noted that a number of autosomal genes display random monoallelic expression that is
independent of the parent-of-origin imprinting process . It was also assumed that DNA
methylation was complementary on both alleles across the genome. Two major studies
demonstrated allelic skewing of DNA methylation and downstream effect on gene
expression. Schalkwyk et al. performed a genome-wide survey of allelic skewing of DNA
methylation in a cohort of lymphocyte samples with the aim of identifying differentially
methylated regions associated with DNA sequence variation acting in cis.

2.3.Aβ Homeostasis as a Target of Environmental Factors

Environmental factors such as diet (fat-rich), heavy metals, biogenic metals and pesticides
have been involved in AD development due to their ability to disrupt metabolic pathways
involved in the homeostasis of Aβ. In addition, factors such as lifestyle (antioxidants and
exercise) can prevent AD development (Figure 1). Many of these environmental factors
are oxidative agents acting through different mechanisms as discussed later. The brain is
particularly vulnerable to oxidative stress do to its high glucose-based metabolic rate, low
levels of antioxidants, high levels of polyunsaturated fatty acids, and high enzymatic
activities related to transition metals that catalyze the formation of free radicals . In
addition, micromolar concentrations of Aβ induce the formation of H 2O2 in culture cells
leading to neurotoxicity, and the presence of some antioxidant enzymes prevents the
toxicity of the peptide . The mechanism by which Aβ generates free radicals is not known,
and other endogenous factors also generate reactive oxygen species (ROS) in AD. For
instance, the ion Fe3+, which is at high concentrations in NFTs and Aβ-aggregates,
catalyzes the formation of reactive species such as H2O2, as well as advanced glycation
end products (AGE) that are related to neurodegeneration
Figure 1. Environmental factors associated with Alzheimer’s disease (AD) development
through different mechanisms. Several factors including metals, pesticides,
nanoparticles, and diet can affect the two targets of AD such as Aβ generation and Tau
phosphorylation. The figure depicts the molecular targets than can be modified at
different levels following the amyloid hypothesis that ends in Aβ senile plaques
formation (upper part) or the hyperphosphorylation of Tau protein and its subsequent
deposition as neurofibrillary tangles (NFTs) (lower part). For more detail see the text.

2.4.Tau Hyperphosphorylation by Environmental Factors

Several environmental factors have shown to mediate AD development through alterations

on Tau phosphorylation and/or aggregation (Figure 1).
Metals. In vivo and in vitro studies have suggested the potential of Hg to induce
P-Tau reported an increased neuronal death and more migrating astrocytes in cerebral
cortex of male mice exposed to MeHg (30 ppm, drinking water), as well as increased
levels of P-Tau mediated by c-jun N-terminal kinase (JNK; . An in vitro study showed that
inorganic Hg (50 µg/dL/30 min) increased P-Tau in SH-SY5Y cells by a ROS-dependent
mechanism, which was reverted by the co-treatment with the antioxidant melatonin
Another study demonstrated that Hg ions coordinate with Cys291 of the second repeated
(R2) of the MT-binding domain of Tau increasing the heparin-induced aggregation, and a
conformational change in Tau demonstrated by circular dicroism (CD) analysis . On the
other hand, Cd appears to play a role in Tau hypothesis since it promotes the aggregation
of this protein. It was shown that Cd (II) accelerates heparin-induced aggregation of the
third repeated (R3) of Tau. The binding of Cd (II) to the dimeric R3 produces changes on
its conformation demonstrated by CD.
2.5.Early Exposure to Environmental Factors and AD or PD Development:
Epigenetic Evidence

Epigenetic DNA modifications include DNA methylation, histone post-translational

modifications (mainly acetylation) and. DNA methylation is one of the most studied
epigenetic modifications that influence the gene expression. It involves the addition of
methyl groups to cytosine bases located at cytosine–phosphate–guanine (CpG) sites by the
action of DNA methyl transferases (DNMTs). Alterations in DNA methylation on the
promoter regions of genes regulate the gene expression of important processes such as
embryonic development, cellular differentiation and aging. Increasing evidence suggests
that epigenetic changes in the developing embryo that may play important roles in the
susceptibility to diseases in later life (imprinted disease phenotypes) result from maternal
exposures to environmental stimuli at critical periods of development. This suggests that a
short exposure to chemicals could be memorized through epigenetic mechanisms long after
the chemical trigger has gone , and recent studies have suggested that an epigenetic
component could be involved in neurodegenerative diseases related to environmental factor.
The latent brain expression of genes observed in animals developmentally exposed to an
environmental contaminant may be mediated through epigenetic pathways that are
regulated via the DNA methylation. While the conditions leading to early life hypo- or
hyper-methylation of specific genes are not known, both can induce oxidative DNA
damage; for instance the hypo-methylation of APP gene increases its expression driving the
overproduction of APP and Aβ levels, which in turn facilitate the ROS production
damaging the DNA, and producing neuronal loss. While the hyper-methylation affects the
gene transcription and DNA repair pathways. Therefore, both changes in DNA methylation
can impact gene expression and imprint susceptibility to oxidative DNA damage in the aged
brain Thus, it is suggested that Pb interferes with the DNA methylating capacity, thus
altering the expression of AD-related genes. The study performed in aged monkeys
developmentally exposed to Pb revealed a reduced activity of brain Dnmt, and the exposure
of mouse primary cells from the cerebral cortex to Pb (0.1 µM) resulted in a similar effect
on Dnmt1 activity a week after 24 h-treatment). Also, showed a significant latent increase
in AD biomarkers an a reduction in the protein and mRNA levels of DNA methylating
enzymes Dnmt1 and Dnmt3a, and methyl CpG binding protein 2 (MeCP2) in differentiated
SH-SY5Y cells treated with Pb (5–100 µM/48 h) and analyzed 6 days later Aberrant CpG
methylation in APP, Tau and GSK3β genes was reported in post-mortem brainsIn addition,
it suggested that reduced levels of CpG methylation in the promoter of APP could be
mediated by the oxidation of guanine (8-oxdG this is because the oxidation of guanine in
CpG dinucleotides inhibits adjacent cytosine methylation .
On the other hand, Cd, another metal involved in AD pathology, reduces the enzymatic
activity of Dnmt in rat liver cell cultures but this effect has not been evaluated in cerebral
cells. While a study showed that subchronic As exposure (3 and 36 ppm/from gestation
until 4 months of age) altered the methylation of genes involved in neuronal plasticity,
including reelin (RELN) and protein phosphatase 1 (PP1), which was associated with
memory deficits . Regarding other compounds, the perinatal exposure to permethrin (34
mg/Kg/daily, by gavage from postnatal day 6–21) to mice showed altered brain functions
including biomarkers of maintenance of dopaminergic neurons, and impairment of spatial
memory at 6 months of age .

The relation between epigenetic modifications and PD has been less studied; however, a
potential role of DNA methylation in the promoter of α-syn encoding gene (SNCA) in the
neuropathogenesis of PD has been suggested, considering that α-syn is a fundamental
component of LB, the main hallmark of PD . A DNA hypomethylation of SNCA was
reported in the substantia nigra of sporadic PD patients, suggesting that it might contribute
to the dysregulation of SNCA . In addition, increased SNCA mRNA levels were observed in
SNpc of PD and reduced levels of Dnmt1 have been observed in postmortem brains from
PD and dementia with LB (DLB) patients, as well as in brains of α-syn transgenic mice;
authors suggest that this effect could be a novel mechanism of epigenetic dysregulation in
LB-related diseases such as PD . Finally, a lesser degree of methyation of the TNFα
promoter, a key inflammatory cytokine associated with dopaminergic cell death was
observed in the SNpc from PD patients, predisposing to an increase neuronal vulnerability
to inflammatory reactions
Environmental factors associated with an increased risk of PD such as pesticides can alter
the expression of genes by epigenetic mechanisms It was reported that pre-treatment with 5-
aza-2’deoxycytidine (5’-aza-dC, a DNMT inhibitor) exacerbated the dopaminergic neuron
damage induced by PQ, MPP+, 6-hydroxydopamine (6-OHDA) and rotenone treatment, and
induced oxidative stress, the transcriptional up-regulation of α-syn, and demethylation of
the α-syn promoter . Likewise, the folate deficiency sensitizes mice to MPTP-induced PD-
like pathology and motor dysfunctionit is well known that folate deficiency alters the
development of human nervous system .
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