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Schizophrenia
(SCZ) and Parkinson’s disease (PD) are two major problems of health worldwide,
in which genomic and environmental factors are involved. In both brain
disorders there is a severe compromise of the dopaminergic system, which is the
target of classical therapeutic intervention. We have studied chromosomal
aberrations (CAs) and epigenetic dysfunction in SCZ and PD cases from South
India. CAs were found in most cases of SCZ, especially deletions (42.17%),
duplications (13.25%) and inversions (44.58%), with an average of 4.15
CAs/patient, affecting Chr. 1, 2, 3, 4, 6,7, 9, 10, 11, 13, 15, 16, 22 and X.
In PD, deletions (41.38%), duplications (20.69%) and inversions (37.93%) were
present, with an average of 5.8 CAs/patient. As compared to controls, the
frequency of CAs was significantly higher in SCZ (5.36 ± 2.46 vs. 0.44 ± 0.83,
p<0.0001) and PD (5.8 ± 1.73 vs 0.32 ± 0.89, p<0.001). No significant
differences were found in the distribution and frequency of polymorphic
variants in the brain-derived neurotrophic factor (BDNF) gene among SCZ, PD and controls. However, CpG islands in
promoters I and IV of the BDNF gene
were found to be hypermethylated in SCZ, but not in PD or in healthy
age-matched controls. Significant changes in GABA and transferrin levels were
also found in SCZ and PD as compared to control subjects. These results show
important cytogenetic anomalies in extensive regions of the genome in both SCZ
and PD, and epigenetic changes in the BDNF
gene in SCZ, with potential repercussions in pathogenesis and pharmacogenetics.
Keywords: BDNF, Biomarker, Cytogenetics, Epigenetics,
GABA, Parkinson’s disease, Schizophrenia, Transferrin
INTRODUCTION
Schizophrenia (SCZ) is a major mental health problem, and Parkinson’s
disease (PD) represents the second most important neurodegenerative disorder,
after Alzheimer’s disease in developed societies. The worldwide prevalence of
SCZ ranges between 0.5% and 1%, with the first episode at 21 years of age in
men and 27 years of age in women. Approximately one-third of the cases will
attempt suicide and, eventually, about 1 out of 10 will take their own lives.
Global costs for SCZ are estimated to be over $6 billion in the USA [1]. SCZ is
among the most disabling of mental disorders. Several neurobiological
hypotheses have been postulated as responsible for SCZ pathogenesis: polygenic/ multifactorial genomic
defects, intrauterine and perinatal environment-genome interactions,
neurodevelopmental defects, dopaminergic, cholinergic, serotonergic,
gamma-aminobutyric acid (GABAergic), neuropeptidergic and
glutamatergic/N-Methyl-D-Aspartate (NMDA) dysfunctions, seasonal infection,
neuroimmune dysfunction, and epigenetic dysregulation [2,3]. SCZ has a
heritability estimated at 60-90%. Genetic studies in SCZ have revealed the
presence of chromosome anomalies, copy number variants, multiple
single-nucleotide polymorphisms of susceptibility distributed across the human
genome, mitochondrial DNA mutations, and epigenetic phenomena [1,4-9].
PD shows a prevalence ranging from 35.8 per 100,000 to 12,500 per
100,000, with annual incidence estimates ranging from 1.5 per 100,000 to 346
per 100,000 in different countries [10-12]. Several pathogenic risk factors
(toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage,
genomic defects) have been associated with PD. PD neuropathology is
characterized by a selective loss of dopaminergic neurons in the substantia
nigra pars compacta and Lewy body deposition, with widespread involvement of
other CNS structures and peripheral tissues [13,14]. PD is a form of
multi-systemic α-synucleinopathy with Lewy bodies deposited in midbrain.
Descriptive phenomena to explain in part this neuropathological phenotype
include the following: (i) genomic factors, (ii) epigenetic changes, (iii)
toxic factors, (iv) oxidative stress anomalies, (v)
neuroimmune/neuroinflammatory reactions, (vi) hypoxic-ischemic conditions,
(vii) metabolic deficiencies, and (viii) ubiquitin-proteasome system
dysfunction [15-21]; all these conditions leading to protein misfolding and
aggregation and premature neuronal death.
Mutations in a series of primary genes are known to cause autosomal
dominant and recessive forms of PD [19-22]. Mutations in some genes (e.g., SNCA, PARK2, PINK1, PARK7, LRRK2, BST1, MAPT)
might be causative in familial forms of PD whereas diverse genetic defects in
other loci might represent susceptibility loci associated with sporadic PD
without family history [20]. Mendelian variants with high penetrance (e.g., SNCA,
LRRK2, PARKIN, PINK1, PARK7 genes), explain less than
10% of familial PD [23]. Over the past decade, several genome-wide association
studies (GWAS) have contributed to clarify the contribution of genetic factors
to the pathogenesis of PD in the Caucasian population and in other ethnic
groups [24-30]. In a recent meta-analysis of PD GWAS with over 7 million
variants, 26 loci have shown significant association with PD. Replication
studies confirmed 24 SNPs, and conditional analyses within loci showed 4 loci (GBA, GAK-DGKQ, SNCA, HLA) with a
secondary independent risk variant [31]. Significant associations at different
loci (DLG2, SIPA1L2, STK39, VPS13C, RIT2,
BST1, PARK16) have been found in Asians vs Europeans, together with allelic
heterogeneity at LRRK2 and at 6 other
loci, including MAPT and GBA-SYT11 [30]. The expression of PD
genes is regulated by the epigenetic machinery (DNA methylation,
histone/chromatin modifications, miRNA dysregulation) [32-39].
Dysfunction of the dopaminergic system in the brain is associated with
SCZ and PD. Catecholamines are processed by three main nuclei (A8-retrobulbal,
A9-substantia nigra pars compacta, A10-ventral tegmental area) arranged in the
mesencephalic region where the mesostriatal, mesolimbic and mesocortical pathways
are organized [40,41]. Midbrain
dopaminergic neurons in the ventral tegmental area and noradrenergic neurons in
the locus coeruleus are major sources of dopamine and noradrenaline to the
prefrontal cortex, where these amines regulate cognition, behavior, and
psychomotor function [42,43]. As a
classical concept, brain hyperdopaminergia is associated with SCZ and psychotic
disorders in which most neuroleptic drugs exert an inhibitory effect on the
hyperactivated dopaminergic system, potentially causing Parkinsonian disorders
after long-term treatment [15];
and brain hypodopaminergia is associated with PD, where L-DOPA and other
anti-parkinsonian drugs enhance the activity of a deficient dopaminergic system
[44-46], chronically leading to
potential psychotic disorders in PD. Genomic and epigenomic characterization of
these antagonistic biophenotypes, in terms of dopaminergic neurotransmission
(hyperdopaminergia vs hypodopaminergia) as well as other neurotransmitters
involved in higher activities of the central nervous system and psychomotor
function, would help to better understand pathogenesis and implement
personalized therapeutic procedures [44-47].
In the present study, our main aims are the
following: (i) characterization of cytogenetic aberrations in SCZ and PD; (ii)
genetic assessment of brain-derived neurotrophic factor (BDNF) variants, especially at promoters I and IV of this gene;
(iii) DNA methylation analysis of promoters I and IV of the BDNF gene; and (iv) biochemical
assessment of GABA and transferrin levels in SCZ and PD. To our knowledge, this is probably
the first study on cytogenetics and epigenetics performed in a selected
population of SCZ and PD patients from India Tamil Nadu and Kerala States.
MATERIAL
AND METHODS
Patients and
controls
Four groups of subjects were established: (i) Patients with
schizophrenia (SCZ)(N=20); age, 44.8 ± 24.3 years; (ii) age-matched controls
for SCZ (CS)(N=20); age, 45.8 ± 21.9 years); (iii) patients with Parkinson’s
disease (PD)(N=5); age, 53.0 ± 15.1 years; and (iv) age-matched controls for PD
(CP)(N=5); age, 52.6 ± 13.2 years. All controls belonged to the same ethnic
origin as the recruited patients. The study followed the ethical procedures of
the Chaithanya Mental Health Care Center, Cochin, Kerala, India. Informed
consent was obtained from the subjects assuring the use of blood for research
purposes alone. The work was carried out in accordance with the ethical standards of
the 1964 Declaration of Helsinki.
Sample collection
The inclusion criteria for the classification of SCZ and PD was made by
using the Structured Clinical Interview for DSM-IV questionnaire (SCID) and the
39-Item Parkinson’s Disease Questionnaire (PDQ-39), respectively. Pedigree
charts were drawn to understand the familial background and the inheritance
pattern of participants. A blood sample of 10 mL was drawn by venipuncture from
an antecubital vein following administration of an anesthetic ointment. The
blood was collected in two sterile tubes containing EDTA and sodium heparin.
The collected samples were transported to the cytogenetic laboratory within 5
hours and were set aside for 24 hrs at room temperature prior to processing.
Cytogenetic analysis
All chemical reagents were purchased from Sigma Chemical (St. Louis,
MO), except for colcemid, which was obtained from Gibco Laboratory (Grand
Island, NY). The blood samples were set up to establish cell cultures according
to the standard procedures of our laboratory. Briefly, 0.5 mL whole blood was
added to 4.5 mL RPMI 1640 medium supplemented with 10% fetal bovine serum, 2 mM
L-glutamine, 1% streptomycin-penicillin antibiotics and 0.2 mL reagent-grade
phytohemagglutinin, and incubated at 37˚C. After 71 hrs, the cultures were
treated with 0.1 µg/mL colcemid to block cells in mitosis. The lymphocytes were
harvested at 72 hrs by centrifuging cells to remove culture medium (800-1,000
rpm, 7 min) to which hypotonic solution (KCl 0.075 M) was added at room
temperature and incubated for 20 min to swell the cells. The cells were treated
twice with fixative (methanol and acetic acid [3: 1 vol/vol]). Cytological
preparations were made by placing two to three drops of the concentrated cell
suspension onto slides wetted with ice-cold acetic acid (60%) and were
carefully dried on a hot plate (56˚C for 2 min). For Chromosomal Aberration
(CA) analysis, 100 complete metaphase cells of the first cell cycle were
evaluated under a microscope (x100) to identify numerical and structural CA
according to the International System for Human Cytogenetic Nomenclature
(ISCN). Data were registered on master tables and later transferred to a
computer file.
GABA and Transferrin
Determination
GABA and transferrin determinations were carried out with an ELISA kit
(Abcam, India). 50 µL of derivatized sample and specific antiserum were
incubated overnight at 4 - 8°C. After three wash cycles with 300 µL wash
buffer, 100 µL enzyme conjugate was incubated in a shaker for 30 min at RT, and
the absorbance of 100 µL substrate was measured at 450 nm after the addition of
stop solution.
Genotyping
Whole genomic DNA was collected by following kit protocol (Bangalore
Genei-Frozen blood DNA extraction kit) and run on 1% agarose at 50V. The ratio
of OD 260 and OD 280 was obtained to estimate the purity of DNA. The bisulfate
conversion of extracted DNA was performed to change the unmethylated cytosines
to uracil but leaving the methylated cytosine residues as such, without any
chemical modifications. For the conversion, 1 µg of DNA was denatured by adding
it to 50 µL of 0.2M NaOH and incubated for 10 minutes at 37ºC. 30 µL of freshly
prepared 10 mM hydroquinone and 520 µL of 3M sodium bisulfite (pH 5.0) was
added, mixed and incubated at 50ºC for 16 hrs. Modified DNA was purified and
eluded into 50 µL of water. DNA was further subjected to 0.3M NaOH treatment
for five minutes followed by ethanol precipitation. The purified DNA was stored
in MilliQ water for further use.
Methylation-specific
PCR amplification
Primers were specifically designed to amplify the methylated strands of
CpG islands of promotor I (F 5’-AGGGAAAGTTGTTGGGCTGG-3’; R
5’-CTCGCTGTTTACGTGACCA-3’) and promotor IV (F 5’-ATGACGGTGATAGGCTGCTC-3’; R
5’-TCTCCCAGTTCTGCGTTCAG-3’) of the BDNF
gene using Methprep Tool. The reaction volume used included 4.0 μL of 200 ng
template DNA, 1.0 μL of forward and reverse primer each, 12.5 μL of 2X
MasterMix for a total reaction volume of 25 μL. An initial denaturing step at
95°C (10 min) followed by 30 cycles of 95°C (30s) denaturation, 60°C (30s)
annealing, 72°C (1 min) extension and a final elongation step of 72°C (10 min)
was carried out. The PCR products were electrophoresed on 1% agarose gels
containing EtBr and viewed under ultraviolet light.
STATISTICAL
ANALYSIS
Data were analyzed by using IBM SPSS Statistics 20 and SigmaPlot 10.0
Software. Comparisons between groups were studied by t-Test, Mann-Whitney Rank
Sum Test, Chi Square without Yates correction and Fisher exact, and Pearson
Correlation Analysis (Nonlinear Regression, Durbin-Watson Statistic, Normality
Test, Constant Variance Test, 95% Confidence). All values are expressed as mean
± SD, and the degree of significance is considered when p<0.05.
RESULTS
Cytogenetic
analysis of SCZ patients revealed that major chromosomal aberrations (MCA)(2.10
± 0.96 vs 0.30 ± 0.47, p<0.001), minor CAs (mCA)(3.10 ± 0.91 vs. 0.15 ±
0.37, p<0.001) and total CAs (TCA)(5.20 ± 1.39, p<0.001) were
significantly more frequent in SCZ than in controls (Figure 1). CAs were present in Chr. 1, 2, 3, 4, 6, 7, 9, 10, 11,
13, 15, 16, 22 and X (Figure 2),
showing deletions (Del)(42.17%; 1.75 Del/patient), duplications (Dupl)(13.25%;
0.55 Dupl/patient), and inversions (Inv)(44.58%; 1.85 Inv/patient), with an
average of 4.15 CA/patient. About 45% of CAs affected the short (p) arms of
chromosomes, whereas 55% of CAs were identified in the long (q) arms; 54.3% of
Del were on p and 45.7% on q arms; 45.45% of Dupl were on p and 54.56% on q
arms; and 35.14% of Inv were on p and 64.86% on q arms (Figure 2).
Cytogenetic
analysis of PD cases showed that the frequency of MCA (3.40 ± 1.34 vs 0.20 ±
0.44, p<0.001), mCA (2.60 ± 1.14 vs 0.20 ± 0.44, p<0.001) and TCA (6.00 ±
2.12 vs 0.40 ± 0.55, p<0.001) were significantly higher in PD than in
controls, with 5.8 CAs/patient (Figure 3).
Del (41.38%)(2.4 Del/patient) were present in Chr. 1q, 5q, 6q, 8p, 12q, 17p,
and 22d; Dup (20.69%) (1.2 Dup/patient) in Chr. 13q and 20p12.3; and Inv
(37.93%) (2.2 Inv/patient) in Chr. 1q, 4q, 5q and 17q (Figure 2 and 4).
Correlation analysis of CAs vs age showed that
there is an age-related increase in CAs in SCZ (p=0.04), but not in PD (Figure 5).
No relevant differences have been found in the distribution and
frequency of BDNF genotypes in SCZ
and PD with respect to controls (Table
1); however, the promoter I and
IV regions of the BDNF gene
exhibited a hypermethylation profile, which was absent in PD and controls (Figure 6).
GABA levels were found to be significantly higher in SCZ (149.55 ±
37.84 pmol/mL) and PD (135.20 ± 3.34 pmol/mL) than in controls (CS: 119.60 ±
9.62 pmol/mL; p=0.003; CP: 121.60 ± 8.44 pmol/mL; p=0.01) (Figure 7), and these differences were unrelated to age (Figure 8). Similarly, transferrin
showed higher levels in SCZ (2.67 ± 0.26 mg/mL) than in controls (2.40 ± 0.40
mg/mL; p=0.02); and, to a lesser extent, transferrin levels tended to be higher
in PD (2.70 ± 0.18 mg/mL) than in controls (2.30 ± 0.38 mg/mL; p=0.06)(Figure 9), with no significant
age-related effect among patients, but with a great variability among CS and CP
(Figure 10).
DISCUSSION
The human genome is enriched in interspersed segmental duplications
that sensitize approximately 10% of our genome to recurrent microdeletions and
microduplications as a result of unequal crossing-over. Studies of common
complex genetic disease show that a subset of these recurrent events plays an
important role in autism, SCZ and epilepsy [48]. Diverse cytogenetic
abnormalities and over 1,000 genetic defects, reported in about 2,400 studies,
have been associated with SCZ during the past two decades [3,8,49]. Structural
variations of DNA, such as copy number variations (CNVs), contribute both to
normal genomic
variability and to risk for SCZ and many other brain disorders. CNVs at
genome loci 1q21.1, 2p16.3, 3q29, 15q11.2, 15q13.3, 16p13.1 and 22q11.2 are
currently associated with SCZ [50]. Recurrent submicroscopic copy number
changes include deletions at 1q21.11, 15q11.3, 15q13.3, and the recurrent CNV
at the 2p16.3 neurexin 1 locus [51]. Genome-wide studies of CNVs show
replicated associations of SCZ with rare 1q21.1 and 15q13.3 deletions. Complex
mutational mechanisms involving rare CNVs elevate risk for SCZ, especially
developmental forms of the disease. Most CNVs, including 22q11.2 deletions,
appear to account for up to 2% of SCZ cases [52]. In previous studies we found
chromosome banding imbalance in several loci at Chr. 1q21.1, 2p24.3, 3q29, 6p,
7q, 9p21.3, 10p, 11q, 13q,15q11.2,16p1.1,22q, and Xp [53]. There are other
studies that also implicate the chromosomal region 11q21-22 as containing genes
with increased liability for SCZ. Some balanced translocations at q14.3, q21,
q22.3 and q25 sites of chromosome 11 were found in SCZ and in other psychiatric
disorders [54-56]. In the present study, we replicated previous findings and
identified deletions at 1q, 7q, 11q and 22q which meet sufficient and
arbitrarily defined criteria as potential susceptibility loci for SCZ [57,58].
In our sample, the rate of deletions and inversions is quantitatively similar
in SCZ, whereas the duplication rate is substantially lower than that of
deletions and inversions (Figure 2).
Recent studies in the Han Southern Chinese population identified four CNVs,
including two deletions and two duplications. The 16p11.2 duplication from
29.3 Mb to 29.6 Mb was detected in four cases (0.84%) and one control
(0.098%) [59]. Evidence has been confirmed for genome-wide significant
associations with SCZ in the Han Chinese population for three loci, at 2p16.1
(rs1051061, in an exon of VRK2),
6p22.1 (rs115070292 in an intron of GABBR1)
and 10q24.32 (rs10883795 in an intron of AS3MT;
rs10883765 at an intron of ARL3)
[60]. It has been postulated that CNVs may act to impair inhibitory learning in
SCZ, potentially contributing to the development of core symptoms of the
disorder [61]. The age-related increase of CAs in SCZ observed in our sample (Figure 5) may suggest that some CAs
might result from de novo formation
mutations associated with either the psychotic phenotype and/or the influence
of neuroleptic drugs.
CNVs have been reported in major neurodegenerative disorders, including
PD [62,63]. Using high-resolution arrays in 16 CNV-PD genes, it has been found
that some PD loci are significantly enriched. For instance, PARK2 is under heavy burden with ~1% of
the population containing CNV in the exonic region; and there is a complex
interaction of molecules forming a major hub by the α-synuclein, whose direct
interactors, LRRK2, PARK2 and ATP13A2 are under CNV influence.
According to these results, it was hypothesized that CNVs may not be the
initiating event in the pathogenesis of PD, remaining latent until additional
secondary hits are acquired [64]. In our small sample, deletions (1.40 Del/Pt),
duplications (0.6 Dup/Pt) and inversions (0.81 Inv/Pt) (Figure 4) were significantly over-represented in PD as compared to
controls, indicating that PD-related neurodegeneration is associated with some
CAs (Figure 3); however, the limited
number of cases does not allow any relevant conclusion.
Epigenetic changes (DNA methylation, histone modifications, miRNA
dysregulation) have been implicated in neuropsychiatric and neurodegenerative
disorders [65-67]. SCZ and other neurodevelopmental disorders are associated
with abnormalities in multiple epigenetic mechanisms, resulting in altered gene
expression during development and adulthood [66]. Epigenetics-related
disruption of the dopamine, NMDA, and GABA signaling pathways are important
events in SCZ phenotype [66]. DNA methylation plays a pivotal role in SCZ
pathogenesis. Recent studies identified 2,014 CpGs as GWAS risk loci with
differential methylation profile in SCZ, and 1,689 hypomethylated genes.
Hypermethylated genes include GNA13, CAPNS1, GABPB2, GIT2, LEFTY1, NDUFA10, MIOS,
MPHOSPH6, PRDM14 and RFWD2. The
hypermethylated promoters of a series of pathways (TNF alpha, PDGFR-beta
signaling, TGF beta Receptor, VEGFR1 and VEGFR2 signaling, regulation of
telomerase, hepatocyte growth factor receptor signaling, ErbB1 downstream
signaling and mTOR signaling pathway) suggest that the malfunctioning of these
pathways may contribute to SCZ phenotype [9].
In the human genome, DNA methylation occurs almost exclusively at CpG
dinucleotides. The cytosine residue of a CpG dinucleotide can be covalently
modified by adding a methyl group to its carbon-5 atom resulting in
5-methylcytosine. The methyl group is transferred from S-adenosyl-L-methionine
to a cytosine residue via DNA methyltransferases. CpG dinucleotides are
unevenly distributed throughout the genome and are generally methylated. Some
CpG dinucleotides are clustered in regions known as CpG-islands, which can span
hundreds to thousands of base pairs and are generally unmethylated [68]. A
direct role of DNA methylation in the regulation of this class of promoters
predicts a correlation between their methylation profile and their level of
expression. CpG-poor promoters are frequently methylated in the genomes of
gametes and cells during early development. As previously stated, these genes
are always tissue-specific and show precise expression control during
development [69].
Polymorphic variants in the BDNF
gene (11p14.1), located in a region where CAs accumulate in SCZ, have been
associated with obsessive-compulsive disorder [70], eating disorders [71],
bipolar disorder [72], and SCZ [73]. The Val66-to-Met polymorphism showed significant
association for valine (allele G) with SCZ. Haplotype analysis of the Val/Met
SNP and a dinucleotide repeat polymorphism in the promoter region revealed
highly significant underrepresentation of the methionine (Met1) haplotype in
SCZ [73]. The BDNF gene spans 70 kb
and contains 11 exons with transcription start site in 9 exons, each of which
is associated with a functional promoter [74]. The 3′ exon encodes all or most
of the protein, depending on the 5′ exon used. Independent of the 5′ exon
usage, two separate polyadenylation signals in exon IX can be utilized in BDNF transcripts.
BDNF gene expression is under the control of at least nine
alternative tissue-specific promoters linked to separate 5′ exons. In recent
years, epigenetic factors have become an avenue of investigation with some
promise [75], with the complex epigenetic regulation of BDNF showing relevance
in psychiatric disorders [76].
Increased synthesis of neuronal BDNF
correlates with a decrease in CpG methylation within the regulatory region of
the BDNF gene. Increased BDNF transcription involves dissociation
of the MECP2-histone deacetylase-Sin3A repression complex from its promoter. DNA
methylation-related chromatin remodeling is important for activity-dependent
gene regulation that may be critical for neural plasticity [77].
In our study, we did not find any significant difference in the
distribution and frequency of polymorphic variants at BDNF promoters I and IV in SCZ and PD as compared with their
respective controls (Table 1);
however, promoters I and IV of the BDNF
gene were strongly hypermethylated in SCZ, but not in PD or controls (Figure 6). This hypermethylated profile
of BDNF might contribute to
inhibiting the neurotrophic activity of BDNF on dopaminergic neurons, with a
subsequent increase in neurodegeneration.
The methylation status of the BDNF
promoter CpG island I in our study is in agreement with data previously
collected by Matsumoto et al. [69] in Japanese patients. This leads us to
hypothesize that the CpG methylation status of promotor I of the BDNF gene might represent an epigenetic
biomarker of SCZ pathophenotype. In our study, the promoter IV of the BDNF gene
was also found to be hypermethylated; however, this finding was not observed in
the Japanese cases [69]. This fact might reflect ethnic-related epigenetic
variation. A wide range of epigenetic studies on psychiatric diseases have put
forth the idea that the epigenetic alterations are not exclusively limited to
brain tissues but can also be seen in other peripheral tissues, such as
peripheral blood cells [78]. In our study, we detected that both BDNF promotors I and IV were
hypermethylated in peripheral blood cells from patients with SCZ. It might be
possible that the methylation status in brain has a proportional representation
of methylation in peripheral blood cells [79].
BDNF is a distinctive activity-dependent neurotrophin which is involved
in neuroplasticity and has a role in the differentiation of the neurons. Hence,
DNA hypermethylation in this gene might give rise to a wide variety of
phenotypic variations [80]. Despite the clear results obtained in our sample,
it should be noted that our sample has several limitations. First, as medical
history was unavailable for most of the patients, we could not assess the
effect of medication on DNA methylation changes. Second, the difference in
methylation we identified at CpG I-72 was a nominally significant difference (p = 0.033) and could not be detected
after multiple testing corrections. Therefore, further validation studies using
larger and independent samples will be required. In any case, our data are
consistent with previous epigenetic studies, with minor differences [81-84].
Differences may be partly due to ethnic variation, heterogeneity of the sample,
therapeutic regime, and disease stage [84]. Third, our analysis focused on a
few specific CpG sites in BDNF
promoters. Although these CpG sites were carefully chosen based on previous
studies, levels of DNA methylation at other CpG sites in promoters I and IV (as
well as other promoters) in SCZ remain unknown and are worth studying. The
bromodomain containing 1 gene (BRD1)
participates in histone modifying complexes and thereby regulates the
expression of a large number of genes. BRD1
encodes a protein that is essential for embryogenesis and CNS development.
Genetic variants in the BRD1 locus
show association with SCZ and bipolar disorder, and risk alleles in the promoter
region correlate with reduced BRD1
expression. The risk allele of the rs138880 SNP in the BRD1 promoter region correlates with reduced BRD1 expression [85].
Other important epigenetic factors involved in BDNF expression are miRNAs, small noncoding RNAs that post transcriptionally
downregulate expression of target mRNAs by inhibiting their translation or
causing their degradation. The 3’-UTR of the BDNF transcript contains putative binding sites for 26 miRNAs,
including MIR30A and MIR195. Quantitative RT-PCR confirmed down regulation of BDNF mRNA by MIR30A-5p and MIR195 [86].
The role of GABA in SCZ is still unclear, tough it appears that GABA
signaling molecules are critical for both brain development and SCZ
pathogenesis [87]. GABA is an inhibitory neurotransmitter which is synthesized
from glutamate by glutamic acid decarboxylase (GAD), derived from two genes, GAD1 and GAD2. GAD1 is expressed as both GAD67
and GAD25 mRNA transcripts. GAD67 mRNA shows a lower expression
level in SCZ, and GAD25 mRNA is
expressed in fetal brain, probably regulating neurodevelopment. GAD25 and GAD67 gene expression levels are reduced in blood cells, and there
is no difference in GAD25 and GAD67 gene expression levels between SCZ
vs controls [88]. Classical studies, reported by Lindefors [89], demonstrate
that the majority of neurons in the striatum (caudate-putamen, dorsal striatum,
nucleus accumbens, ventral striatum) and in striatal projection regions (the
pallidum, the entopeduncular nucleus and substantia nigra reticulata) use GABA
as a neurotransmitter and express glutamic acid decarboxylase (GAD), the
rate-limiting enzyme in the synthesis of GABA. Brain GAD is present in two
isoenzymes, GAD65 and GAD67, a dual system for the control of
neuronal GABA synthesis. Inhibition of dopaminergic transmission in the
striatum by lesion of dopamine neurons or by neuroleptic treatment is followed
by an increased release of GABA and increased expression of GAD67 mRNA in a subpopulation of
striatal medium-sized neurons which project to the globus pallidus, and
increased striatal GAD enzyme activity. Increased dopaminergic transmission by
anti-Parkinsonian drugs is followed by decreased striatal GABA release and
decreased GAD67 mRNA expression in a
subpopulation of medium-sized neurons in the striatum. GABA neurons in the
striatum seem to be under tonic dopaminergic influence. The majority of these
GABA neurons are under inhibitory influence, whereas a small number seem to be
stimulated by dopamine. Specific changes in activity in subpopulations of
striatal GABA neurons probably mediate the dopamine-dependent hypokinetic
syndrome seen in PD and following neuroleptic treatment [89]. Hyde et al. [90]
examined the expression of transcripts derived from three genes related to GABA
signaling [GAD1 (GAD67 and GAD25), SLC12A2 (NKCC1), and SLC12A5 (KCC2)] in the prefrontal cortex (PFC) and hippocampal formation of
a large cohort of nonpsychiatric control human brains across the lifespan and
in patients with SCZ, and found that development and maturation of both the PFC
and hippocampal formation are characterized by progressive switches in
expression from GAD25 to GAD67 and from NKCC1
to KCC2, the former leading to GABA
synthesis, and the latter regulating the switching from excitatory to
inhibitory neurotransmission. In the hippocampal formation, GAD25/GAD67 and NKCC1/KCC2 ratios are increased in SCZ, indicating potential
immaturity of GABA neurotransmission. These mechanisms may justify the
increased levels of GABA in SCZ and PD (Figure
7). Mutations in GABA receptors, especially in gamma-aminobutyric acid type
A receptor alpha1 subunit (GABRA1,
5q34) and gamma-aminobutyric acid type A receptor delta subunit (GABRD, 1p36.33), are mainly associated
with epilepsy [91-93]. However, Balan et al. [94] studied the association of
375 tagged SNPs in genes derived from the GABAergic system, such as GABAA receptor subunit genes, and
GABA-related genes (glutamate decarboxylase genes, GABAergic-marker gene, genes
involved in GABA receptor trafficking and scaffolding) in Japanese SCZ
case-control samples, and found nominal association of SNPs in nine GABA
receptor subunit genes and the GPHN
gene with SCZ. Two SNPs located in the GABRA1
gene, rs4263535 and rs1157122, showed top hits, followed by rs723432 in the GPHN gene. Haplotypes containing
associated variants in GABRA1 but not
GPHN were significantly associated
with SCZ.
Finally, high levels of transferrin (siderophilin) in SCZ and PD may
reflect mild iron metabolism dysfunction. This iron transport 678 aa protein is
a β-globulin with high binding affinity for ferric ions and which enters cells
by receptor (CD71)-mediated endocytosis. HFE
mutations and transferrin C1/C2
polymorphic variants do not appear to represent risk factors for either SCZ or
PD [96]. However, neuroleptic treatment may result in altered glycosylation of
serum proteins, compromising transferrin levels. For instance, olanzapine
treatment results in increased levels of a disialylated biantennary glycan and
reduced levels of a number of disialylated bi- and triantennary glycans on
whole serum glycoproteins [97]. Iron is essential for brain function, and it is
not infrequent to detect iron metabolism abnormalities in neurodegenerative
disorders, such as PD and Alzheimer’s disease, which contribute to accelerating
neurodegeneration. Iron entry into the brain is regulated by the blood-brain
barrier (BBB). NHE9 (SLC9A9) is an endosomal cation/proton antiporter which
regulates this transport system. Ectopic expression of NHE9 in BBB endothelial
cells without external cues induces up regulation of the transferrin receptor
(TfR) and down regulation of ferritin, leading to an increase in iron uptake
[98]. NHE9-GFP localizes to recycling endosomes, where it significantly
alkalinizes luminal pH, elevates uptake of transferrin and the neurotransmitter
glutamate, and stabilizes surface expression of transferrin receptor and GLAST
transporter. Loss-of-function mutations in NHE9
(L236S, S438P and V176I) may contribute to autistic phenotype by modulating
synaptic membrane protein expression and neurotransmitter clearance [99].
Physical and mental fatigue is a very common non-motor symptom in PD. It has
been hypothesized that serotonergic dysfunction and abnormal iron metabolism
are involved in mental fatigue in PD. The levels of serotonin, iron and
transferrin in cerebrospinal fluid have been found increased in Chinese
patients with PD; in contrast, serum serotonin and transferrin levels were
found to be diminished in these patients [100]. In our PD cases, serum
transferrin levels tended to be higher than in controls; however, the limited
number of cases in our sample is insufficient to reach any conclusion. On the
other hand, α-synuclein, the principal protein involved in the pathogenesis of
PD, is expressed widely in the neuroretina, and facilitates the uptake of
transferrin-bound iron (Tf-Fe) by retinal pigment epithelial cells that form
the outer blood-retinal barrier. Absence of α-synuclein results in down-regulation
of ferritin in the neuroretina, indicating depletion of cellular iron stores.
Retinal iron dyshomeostasis due to impaired α-synuclein function may contribute
to PD-related visual symptoms [101]. Consequently, iron metabolism dysfunction
in SCZ and PD cannot be neglected in the clinical setting.
From the results obtained in this study, we can conclude the following:
(i) extensive regions of the human genome show cytogenetic anomalies
(deletions, duplications, inversions) in SCZ and in PD; chromosomal aberrations
tend to increase with age in SCZ; (ii) epigenetic changes in the BDNF gene are represented by
hypermethylation of CpG islands in promoters I and IV in patients with SCZ, but
not in PD; (iii) serum GABA levels are significantly increased in both SCZ and
PD cases; and (iv) transferrin levels are significantly higher in SCZ than in
controls and show a tendency to increase in PD, reflecting mild iron metabolism
dysfunction in both CNS disorders.
ACKNOWLEDGEMENTS
The authors thank the Management of Bharathiar University for providing
infrastructure facilities for this research work and the subjects who
volunteered to take part in this study.
CONFLICT
OF INTEREST
The authors declare that there are no conflicts of interest.
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