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SARS-CoV-2 infection causes asymptomatic to severe human respiratory diseases. Vaccinations are effective only to a certain extent, and the disease recurs with milder symptoms even after booster doses. Hence, we hypothesize that antiviral therapy in conjunction with vaccination is the need of the hour for containing the disease. SARS-CoV-2 enters the host cell through interaction between viral spike (S) protein and human Angiotensin II converting enzyme2 (ACE2). So, any S-protein neutralizing molecule could be a potential antiviral moiety. The interaction-interface architecture indicates that cationic peptides effectively bind to anionic interface residues of S protein-receptor binding domain (S-RBD). Subsequently, we adopted molecular docking and simulation approaches to examine the binding affinity of cationic human α and β defensins, HNP1 and HBD2 with S-RBD. We observed strong hydrogen bonds, electrostatic, salt bridge, and hydrophobic interactions between these defensins and S-RBD with binding energy (BE) of -10.7 kcal/mol. Interestingly, defensins from

BACKGROUND Folate has a pivotal role in maintaining different cellular processes including DNA integrity and neurotransmitter levels. Further, folate deficiency was reported in subjects with neuropsychiatric disorders including autism spectrum disorder (ASD). METHODS AND RESULTS We recruited ASD probands following the Diagnostic and Statistical Manual of Mental Disorder-IV/-5. Severity was assessed by the Childhood Autism Rating Scale2-Standard Test (CARS2-ST). Functional SNPs in reduced folate carrier1 (rs1051266), methylenetetrahydrofolate dehydrogenase (rs2236225), methylenetetrahydrofolate methyltransferase (rs1805087), methylenetetrahydrofolate reductase (rs1801133 and rs1801131), cystathionine-beta- synthase (rs5742905), and serine hydroxymethyltransferase (rs1979277) genes were analyzed in the ASD probands (N = 203), their parents and controls (N = 250) by PCR/TaqMan based methods. Plasma homocysteine and vitamin B12 levels were examined by Enzyme-Linked ImmunoSorbent Assay. Statistical analysis revealed higher frequencies of rs1051266 and rs1805087 "A" alleles (P = 8.233e-005 and P = 0.010 respectively) and rs1051266 "AA" genotype (P = 0.02) in the ASD probands. Gender based stratified analysis revealed higher frequency of rs1051266 "AA" in the male probands (P = 0.001) while frequencies of rs1805087 "A" (P = 0.001) and "AA" (P

Opioid receptor mu1 (OPRM1) is the target of many opioid drugs, and it is known to have affinity toward both endogenous and exogenous opioids, opiate and opioid analgesic drugs. The present study w...

Opioid receptor mu1 (OPRM1) is the target of many opioid drugs, and it is known to have affinity toward both endogenous and exogenous opioids, opiate and opioid analgesic drugs. The present study was undertaken to explore association of single nucleotide polymorphisms (SNPs) in the

Platelet hyperserotonemia in a subset of Autism Spectrum Disorder (ASD) probands, efficacy of selective serotonin reuptake inhibitors (SSRIs) in reducing behavioral deficits and gender-bias in normal serotonin (5-hydroxy tryptamine or 5-HT) synthesis suggest disruption in stringent regulation of serotonin metabolism in ASD. Therefore, we investigated the changes in 5-HT and 5-hydroxy indole acetic acid (5-HIAA) in ASD probands to assess its effect on the behavior of male and female probands. ASD cases (n = 215) were examined using childhood autism rating scale (CARS). Platelet 5-HT (104 cases and 26 controls) and platelet/plasma 5-HIAA (73 cases and 17 controls) were estimated using high performance liquid chromatography coupled with electrochemical detector (HPLC-ECD). In male probands, we observed increase in platelet 5-HT content in association with increase in the score for adaptive responses and increase in platelet 5-HIAA levels with concomitant decline in the score for intellectual response. Age did not influence the neurochemical parameters, but imitation, listening responses and nonverbal communication scores decreased with age. Conversely in female probands, plasma 5-HIAA level significantly attenuated with age, when platelet 5-HT content remained unchanged. Interestingly, platelet/plasma 5-HT and plasma 5-HIAA were higher in female controls. Female probands displayed severe autism-associated behaviors. Overall results indicate gender-bias in 5-HT and 5-HIAA regulation, which probably increases the threshold level of ASD phenotypes in the females, thereby affecting ASD prevalence in a sex-specific manner.

Dopamine transporter (DAT) or solute carrier family 6 member 3 (SLC6A3) is a transmembrane protein regulating dopaminergic neurotransmission. It has been implicated in playing important roles in the dopaminergic reward pathways, and thus, DAT1 is a strong candidate gene for association studies with heroin dependence. A case-control study involving 279 individuals (147 controls and 132 heroin-dependent cases) was conducted. Ten polymorphisms of the DAT1 (SLC6A3) gene were analysed for its association with heroin dependence. Following the Hardy-Weinberg equilibrium (HWE) test, genetic association analyses were performed for the study groups. The post hoc statistical power of the study was 0.655 (65.5%). Single-nucleotide polymorphism (SNP) rs246997 was found to be significantly associated with heroin dependence at allelic, genotypic, and haplotypic levels. A significant difference in the distribution of 11R allele and 10R/11R genotype of rs28363170 between heroin-dependent cases and controls was also observed. Nominal significance at degrees of freedom (df) = 5 was also observed for rs28363170. Five bimarker-based haplotype combinations were also found to be associated with heroin dependence. For the first time, 13R allele (7R/13R genotype) and 14R allele (7R/14R genotype) were identified for rs3836790 in the population. The study also reports that the 11R allele and 10R/11R genotype of rs28363170 is associated with protection against heroin dependence. 7R and 6R alleles were also found to be the common alleles of rs3836790 in the study population. The study provides evidence for the association of polymorphisms of DAT1 (SLC6A3) with heroin dependence.

Huntington’s disease (HD) is caused due to an abnormal expansion of polyglutamine repeats in the first exon of huntingtin gene. The mutation in huntingtin causes abnormalities in the functioning of protein, leading to deleterious effects ultimately to the demise of specific neuronal cells. The disease is inherited in an autosomal dominant manner and leads to a plethora of neuropsychiatric behaviour and neuronal cell death mainly in striatal and cortical regions of the brain, eventually leading to death of the individual. The discovery of the mutant gene led to a surge in molecular diagnostics of the disease and in making different transgenic models in different organisms to understand the function of wild-type and mutant proteins. Despite difficult challenges, there has been a significant increase in understanding the functioning of the protein in normal and other gain-of-function interactions in mutant form. However, there have been no significant improvements in treatments of the patients suffering from this ailment and most of the treatment is still symptomatic. HD warrants more attention towards better understanding and treatment as more advancement in molecular diagnostics and therapeutic interventions are available. Several different transgenic models are available in different organisms, ranging from fruit flies to primate monkeys, for studies on understanding the pathogenicity of the mutant gene. It is the right time to assess the advancement in the field and try new strategies for neuroprotection using key pathways as target. The present review highlights the key ingredients of pathology in the HD and discusses important studies for drug trials and future goals for therapeutic interventions.

An etiologically complex disorder, Attention Deficit Hyperactivity Disorder (ADHD), is often associated with various levels of cognitive deficit. Folate/vitamin B9 is crucial for numerous biochemical pathways including neural stem cell proliferation and differentiation, regulation of gene expression, neurotransmitter synthesis, myelin synthesis and repair, etc. and a scarcity has often been linked to cognitive deficit. Our pilot study in the field revealed significant association of few genetic variants with ADHD. Mild hyperhomocysteinemia and vitamin B12 deficiency was also noticed in the probands. In the present study additional genetic variants, folate and vitamin B6, which may affect folate-homocysteine metabolic pathway, were investigated in 866 individuals including nuclear families with ADHD probands (N=221) and ethnically matched controls (N=286) to find out whether ADHD associated traits are affected by these factors. Population based analysis revealed significant over representation of MTRR rs1801394 "G" allele and "GG" genotype in all as well as male probands. Stratified analysis showed significantly higher frequency of RFC1 rs1051266 and BHMT rs3733890 "AG" genotypes in full term and prematurely delivered ADHD probands respectively. Probands with rs1801394 "GG" genotype and BHMT rs3733890 "G" allele showed association with hyperhomocysteinemia. MTHFR rs1801131, MTR rs1805087 and BHMT rs3733890 also showed association with ADHD index. While rs1051266, rs1801131, and rs1805087 showed association with behavioral problems, rs3733890 was associated with ODD score. Conduct problem exhibited association with RFC1 rs1051266, MTHFR rs1801133 and MTRR rs1801394. Gene-gene interaction analysis revealed positive synergistic interactions between rs1051266, rs1801131 and rs1801394 in the probands as compared to the controls. It can be inferred from the data obtained that folate system genetic variants and mild hyperhomocysteimenia may affect ADHD associated traits by attenuating folate metabolism.

We investigated role of the folate-homocysteine metabolic pathway in the etiology of attention-deficit hyperactivity disorder (ADHD) due to its importance in maintaining DNA integrity as well as neurotransmission. Functional gene variants in MTR (rs1805087), CBS (rs5742905), MTHFR (rs1801133 &rs1801131), MTHFD (rs2236225), RFC1 (rs1051266), plasma vitamin B12, folate and homocysteine were analyzed. rs1805087 'A' showed strong association with ADHD. Vitamin B12 deficiency of ADHD probands (P=0.01) correlated with rs1801133 'T' and rs1805087'GG'. Mild hyperhomocysteinemia (P=0.05) in the probands was associated with rs1805087 'AA'. Probands having rs1805087 'GG' and rs1051266 'G' was more inattentive. Hyperactivity-impulsivity score revealed association with rs5742905 'TT' and rs2236225 'CC', while rs1801133 'CC' showed association with inattentiveness and hyperactivity-impulsivity. rs1801131 exhibited strong synergistic interaction with rs1051266 and rs2236225. This indicated that the folate-homocysteine pathway gene variants may affect ADHD etiology through mild hyperhomocysteinemia and vitamin B12 deficiency, factors known to be associated with cognitive deficit.

Background Pathophysiology of attention-deficit hyperactivity disorder (ADHD) is not known, and therefore the present study investigated mitochondrial defects, if any in cybrids created from patients and control population. Methods To investigate mitochondrial pathology in ADHD, cybrids cell lines were created from ADHD probands and controls by fusing their platelets with ρ0-cells prepared from SH-SY5Y neuroblastoma cell line. Cellular respiration, oxidative stress, mitochondrial membrane potential and morphology were evaluated employing oxygraph, mitochondria-specific fluorescence staining and evaluation by FACS, and immunocytochemistry. HPLC-electrochemical detection, quantitative RT-PCR and Blue Native PAGE were employed respectively for assays of serotonin, mitochondrial ATPase 6/8 subunits levels and complex V activity. Results Significantly low cellular and mitochondrial respiration, ATPase6/8 transcripts levels, mitochondrial complex V activity and loss of mitochondrial membrane potential and elevated oxidative stress were observed in ADHD cybrids. Expression of monoamine oxidizing mitochondrial enzymes, MAO-A and MAO-B levels remained unaffected. Two-fold increase in serotonin level was noted in differentiated cybrid-neurons. Conclusions Since cybrids are shown to replicate mitochondrial defects seen in post-mortem brains, these observed defects in ADHD cybrids strongly suggest mitochondrial pathology in this disorder. General significance Mitochondrial defects are detected in ADHD cybrids created from patients' platelets, implying bioenergetics crisis in the mitochondria could be a contributory factor for ADHD pathology and/or phenotypes.

Serotonergic system participates in various developmental processes and modulation of behaviour. Autism Spectrum Disorder (ASD) is characterized by a range of behavioral symptoms scaling from mild to severe. Abnormal 5-HT synthesis and signalling, platelet hyperserotonemia and amelioration of repetitive behaviours by SSRI are some of the key findings, which reinforced the hypothesis that serotonergic genes might act as ASD susceptible genes. Therefore, genes encoding monoamine oxidases A/B (MAOA/MAOB) received special attention as these genes are located on the X-chromosome and the gene products are responsible for 5-HT degradation. In the present study, we conducted population-based association analysis of eight markers of MAOB with ASD in a study cohort of 203 cases and 236 controls form India and examined its effect on platelet 5-HT content and behaviour. Gender-specific changes were observed for the contrasting LD between pair of markers among cases and controls. Case-control analysis demonstrated over-distribution of major C allele of rs2283728 and rs2283727 in male and female ASD cases respectively. Haplotypic distribution and interaction among markers showed more robust effect in male cases. Interestingly, male ASD cases displayed higher platelet 5-HT content in comparison to the respective controls. Quantitative trait analysis revealed significant correlation of genetic variants and haplotypes of MAOB markers, rs1799836 and rs6324 with increased platelet 5-HT level and CARS scores for specific behavioral symptoms respectively in males. This study suggests that MAOB increases ASD risk in males, possibly through its sex-specific regulatory effect on 5-HT metabolism and behavior.

Objectives: Proper metabolism of the folate is crucial for maintaining DNA integrity, chromosome structure, methylation, as well as gene expression, and thus, folate is speculated to contribute to ...

Huntington's disease (HD) is caused due to an abnormal expansion of polyglutamine repeats in the first exon of huntingtin gene. The mutation in huntingtin causes abnormalities in the functioning of protein, leading to deleterious effects ultimately to the demise of specific neuronal cells.The disease is inherited in an autosomal dominant manner and leads to a plethora of neuropsychiatric behaviour and neuronal cell death mainly in striatal and cortical regions of the brain, eventually leading to death of the individual. The discovery of the mutant gene led to a surge in molecular diagnostics of the disease and in making different transgenic models in different organisms to understand the function of wild-type and mutant proteins. Despite difficult challenges, there has been a significant increase in understanding the functioning of the protein in normal and other gain-of-function interactions in mutant form. However, there have been no significant improvements in treatments of the patients suffering from this ailment and most of the treatment is still symptomatic. HD warrants more attention towards better understanding and treatment as more advancement in molecular diagnostics and therapeutic interventions are available. Several different transgenic models are available in different organisms, ranging from fruit flies to primate monkeys, for studies on understanding the pathogenicity of the mutant gene. It is the right time to assess the advancement in the field and try new strategies for neuroprotection using key pathways as target. The present review highlights the key ingredients of pathology in the HD and discusses important studies for drug trials and future goals for therapeutic interventions.

Quercetin, a strong free radical scavenger, is investigated for neuroprotective effects in a Neuro 2a cell line conditionally transfected with 16Q huntingtin (Htt) and 150Q Htt, which express the protein upon stimulation. Cells were protected from death by a 20-µM dose of quercetin on the second day of Htt induction, but 30-100-µM doses of the drug caused further toxicity in both 16Q and 150Q cells, as indicated by MTT assay and by significant reductions in the number of cells bearing neurites on the second day. A significant decrease in the number of cells containing aggregate was seen in induced 150Q cells treated with 20 µM but not for those treated with 40 or 50 µM quercetin up to 4 days of induction. Mutated Htt (mHtt)-induced reduction in proteasomal activity of the ubiquitin-proteasomal system (UPS) was significantly attenuated by 20 µM quercetin. However, neither mitochondrial membrane potential loss nor colocalization of 20S proteasome with mHtt aggregate was corrected by quercetin treatment. Our results imply that the neuroprotective effect of quercetin arises out of the upregulation of UPS activity, which causes a decrease in the number of mHtt aggregate-harboring cells. The increased neurotoxicity could result from the continued association of mHtt with 20S proteasome and the failure of quercetin to correct mitochondrial membrane potential loss. These results suggest that, although quercetin at a low dose protects against mHtt-mediated cell death, higher doses are toxic to the cells, clearly demarcating a narrow therapeutic window for this dietary flavonoid.

Genetic abnormalities in components important for the folate cycle confer risk for various disorders since adequate folate turnover is necessary for normal methylation, gene expression and chromosome structure. However, the system has rarely been studied in children diagnosed with attention deficit hyperactivity disorder (ADHD). We hypothesized that ADHD related cognitive deficit could be attributed to abnormalities in the folate cycle and explored functional single nucleotide polymorphisms in methylenetetrahydrofolate dehydrogenase (rs2236225), reduced folate carrier (rs1051266), and methylenetetrahydrofolate reductase (rs1801131 and rs1801133) in families with ADHD probands (N = 185) and ethnically matched controls (N = 216) recruited following the DSM-IV. After obtaining informed written consent for participation, peripheral blood was collected for genomic DNA isolation and PCR-based analysis of target sites. Data obtained was analyzed by UNPHASED. Interaction between sites was analyzed by the multi dimensionality reduction (MDR) program. Genotypic frequencies of the Indian population were strikingly different from other ethnic groups. rs1801133 "T" allele showed biased transmission in female probands (p < 0.05). Significant difference in genotypic frequencies for female probands was also noticed. rs1801131 and rs1801133 showed an association with low intelligence quotient (IQ). MDR analysis exhibited independent effects and contribution of these sites to IQ, thus indicating a role of these genes in ADHD related cognitive deficit.

Huntington's disease (HD), an autosomal dominant neurodegenerative movement disorder in which striatal and cortical neurons are mostly affected, has no effective cure existing. A fungal neurotoxin and a potent inhibitor of mitochondrial electron transport chain complex II inhibitor, 3-nitropropionic acid (3-NP) is known to cause HD pathology, including lesions in the striatum and the cortex, and several behavioural syndromes in experimental animals. In the present study we examined the effect of melatonin on motor activities, neuronal morphology as revealed by Nissl and rapid Golgi staining, as well as GABA, glutamate and biogenic amine neurotransmitter levels in 3-NP-induced HD in rats. We found that melatonin (10, 20mg/kg, i.p.) administered 1h prior to 3-NP dose (20mg/kg; daily for 4 days) restored motor coordination ability as shown in gait, beam balancing, swim ability and performance on rotarod. However it failed to reduce 3-NP-induced striatal lesion core area, neuronal damage and the elevated levels of striatal dopamine. Melatonin administration partially restored 3-NP-induced loss of dendritic spines in the striatum and the cortex, and the reduction in cerebellar granule cell, but not hippocampal CA1 neuronal arborization. These findings collectively suggest that melatonin offers beneficial effects in correction of learning related fine motor adjustments, but not in behaviours unrelated to learning, by the restoration of striatal and cortical spines, and cerebellar granule cell arborization.

AIM: Huntington's disease (HD) is an autosomal dominant disorder, for which clinically available drugs offer only symptomatic relief. These prescription drugs are not free of side effects, and the patients usually suffer from anxiety and depression. We investigated quercetin, a dietary flavonoid with free radical scavenging properties, for its beneficial potential if any, in 3‐nitropropionic acid (3‐NP)‐induced HD in rats where both drugs were administered simultaneously. METHODS: Performance of rats on beam balancing, elevated plus maze and gait traits were investigated following 3‐NP and/or quercetin treatments for 4 days. Striatal biogenic amine levels and monoamine oxidase activity were assayed. Striatal sections were examined for Cd11B and glial fibrillary acidic protein immunoreactivity, and for evidences of neuronal lesion. RESULTS: Quercetin significantly attenuated 3‐NP‐induced anxiety, motor coordination deficits, and gait despair. While the dopaminergic hyper‐metabolism was unaffected, quercetin provided a significant reduction of 3‐NP mediated increase in serotonin metabolism. Quercetin failed to affect 3‐NP‐induced striatal neuronal lesion, but decreased microglial proliferation, and increased astrocyte numbers in the lesion core. CONCLUSION: These results taken together suggest that quercetin could be of potential use not only for correcting movement disturbances and anxiety in HD, but also for addressing inflammatory damages.

Rotenone is known to cause progressive dopaminergic neuronal loss in rodents, but it remains unclear how this mitochondrial complex-I inhibitor mediates neurodegeneration specific to substantia nigra pars compacta (SNpc). One of the proposed mechanisms is increased free radical generation owing to mitochondrial electron transport chain dysfunction following complex-I inhibition. The present study examined the role of nitric oxide (NO) and hydroxyl radicals (OH) in mediating rotenone-induced dopaminergic neurotoxicity. Indications of NO involvement are evidenced by inducible nitric oxide synthase (NOS) over-expression, and increased NADPH-diaphorase staining in SNpc neurons 96h following rotenone administration. Treatment of these animals with specific neuronal NOS inhibitor, 7-nitroindazole (7-NI) and non-specific NOS inhibitor, N-ω-nitro-l-argenine methyl ester (l-NAME) caused reversal of rotenone-induced striatal dopamine depletion, and attenuation of the neurotoxin-induced decrease in the number of tyrosine hydroxylase immunoreactive neurons in SNpc, as well as in apomorphine and amphetamine-induced unilateral rotations. Interestingly, the study also demonstrated the contribution of OH in mediating rotenone nigral toxicity since there appeared a significant generation of the reactive oxygen species in vivo 24h following rotenone administration, a copious loss of reduced and oxidized glutathione, and increased superoxide dismutase and catalase activities in the cytosolic fractions of the ipsilateral SNpc area on the 5th day. An OH scavenging capacity of 7-NI and l-NAME in a Fenton-like reaction, as well as complete reversal of the rotenone-induced increases in the antioxidant enzyme activities, and the loss in reduced and oxidized glutathione contents in the SNpc supported OH involvement in rotenone-induced dopaminergic neurotoxicity. While these results strongly suggest the contribution of both OH and NO, resulting in acute oxidative stress culminating in dopaminergic neurodegeneration caused by rotenone, the course of events indicated generation of OH as the primary event in the neurotoxic processes.

We tested quercetin, a dietary bioflavonoid with potent free radical scavenging action and antioxidant activity, for its neuroprotective effects in rotenone-induced hemi-parkinsonian rats. Rats were infused unilaterally with rotenone into the substantia nigra, and quercetin (25-75mg/kg, i.p.) was administered at 12-h intervals for 4days, and analyzed on the 5th day. Amphetamine- or apomorphine-induced unilateral rotations were significantly reduced in quercetin-treated rats, when analyzed on 14th or 16th day post-surgery, respectively. Quercetin possessed potent hydroxyl radical scavenging action in a cells-free, Fenton-like reaction in test tubes, and in isolated mitochondria when measured by salicylate hydroxylation method. We observed dose-dependent attenuation of the rotenone-induced loss in striatal dopamine, and nigral oxidized and reduced glutathione, as well as the increases in endogenous antioxidant enzymes (catalase and superoxide dismutase) activities supporting the notion that quercetin-effect is mediated via its powerful hydroxyl radicals-scavenging and antioxidant actions. Quercetin's dose-dependent ability to up-regulate mitochondrial complex-I activity, as evidenced by NADH-oxidation, and as seen in blue native-polyacrylamide gel electrophoresis (PAGE) staining in both the contra- and ipsi-lateral nigra suggests the containment of reactive oxygen production at the mitochondrial level. Rotenone-induced induction of NADH-diaphorase activity in the nigral neurons, and its attenuation by quercetin pointed to the possible involvement of nitric oxide too. Reversal of neuronal death induced by rotenone as observed by increased tyrosine hydroxylase-positive cells and decreased TdT-mediated dUTP nick end-labeling (TUNEL) staining in the substantia nigra confirmed the potential of quercetin to revamp dopaminergic cells following oxidative stress mediated programmed cell death and neuronal demise. The present study strongly implicates quercetin's potential ability to repair mitochondrial electron transport defects and to up-regulate its function as the basis of neuroprotection observed in a mitochondrial neurotoxin-induced Parkinsonism.

Autism spectrum disorder (ASD) is a childhood neurodevelopmental disorder. During fetal and neonatal brain development, the cues for neurodevelopment are regulated in a well orchestrated manner. Generally, neurotransmitters play a major role in the formation of central nervous system (CNS) and peripheral nervous system (PNS). Glutamate, the excitatory neurotransmitter actively participates in various neurodevelopmental processes through complex regulatory events. Excitatory neurotransmitter signaling via glutamate receptors modulates cognitive functions such as memory and learning, which are usually impaired in ASD. Therefore, glutamate and its regulatory molecules are considered as potential targets for these disorders. Pharmacological, biochemical and behavioral studies reveal possible involvement of glutamatergic system in ASD pathology. An abnormal increase in electrical activity resulting from excessive glutamate signaling causes prolonged alterations in behavior, as commonly seen in ASDs. On the contrary, reports on animal models of hypoglutamatergia demonstrate phenotypes that overlap with features seen in autism. So controversies prevail whether to regard autism as hyper- or hypo-glutamatergic disorder. This paper reviews the role of glutamate and its regulatory proteins such as different receptors, transporters and metabolizing enzymes in the pathophysiology of ASD based on evidences gathered through multidisciplinary approaches. All these information raise the possibility of exploiting glutamatergic neurotransmitter system for future therapeutic interventions for ASD.

Epilepsy is a common neurological condition characterized by unprovoked seizure attacks. Early brain developmental abnormalities involving neuronal migration and lamination are implicated in childhood epilepsy. Reelin, a neuronal-signaling molecule plays a crucial role in these migratory processes. Therefore, reelin gene (RELN), which is located on human chromosome 7q22 is considered as a potential candidate gene for childhood epilepsy. In this study, we recruited 63 patients with childhood-onset epilepsy and 103 healthy controls from West Bengal in India. Genomic DNA isolated from leukocytes of cases and control individuals were used for genotyping analysis of 16 markers of RELN. Case-control analysis revealed significant over-representation of G/C and (G/C+C/C) genotypes, and C allele of exon 22 G/C marker (rs362691) in cases as compared to controls. Pair-wise linkage disequilibrium analysis demonstrated two separate LD blocks with moderately high D' values in epileptic cases. Based on these data, we have carried out haplotype case-control analysis. Even though we found over-representation of A-C haplotype of intron 12 A/C/exon 22 G/C markers and haplotype combination involving G-allele of exon 22 marker in cases and controls, respectively, the overall test was not significant. LD in this region involving this marker was also more robust in epileptic cases. Taken together, the results provide possible evidences for association of exon 22 G/C marker or any marker in the vicinity, which is in LD with this marker with epilepsy in the West Bengal population. Further investigations involving higher sample sizes are warranted to validate the present finding.

Serotonergic system has long been implicated in the aetiology of autism spectrum disorders (ASD), since platelet hyperserotonemia is consistently observed in a subset of autistic patients, who respond well to selective serotonin reuptake inhibitors. Apart from being a neurotransmitter, serotonin functions as a neurotrophic factor directing brain development and as an immunoregulator modulating immune responses. Serotonin transporter (SERT) regulates serotonin level in lymphoid tissues to ensure its proper functioning in innate and adaptive responses. Immunological molecules such as cytokines in turn regulate the transcription and activity of SERT. Dysregulation of serotonergic system could trigger signalling cascades that affect normal neural-immune interactions culminating in neurodevelopmental and neural connectivity defects precipitating behavioural abnormalities, or the disease phenotypes. Therefore, we suggest that a better understanding of the cross talk between serotonergic genes, immune systems and serotonergic neurotransmission will open wider avenues to develop pharmacological leads for addressing the core ASD behavioural deficits.

Autism spectrum disorder (ASD) is a male predominance, behaviorally defined neurodevelopmental disorder which is characterized by impairment in social communication and restricted and repetitive activities. Abnormalities in serotoninergic function play a major role in ASD pathophysiology. Monoamine oxidases, encoded by two X-chromosomal genes MAOA and MAOB regulate the serotonergic function by the degradation of serotonin and other biological amines. Therefore, the objective of present study is to investigate genetic correlation of MAOB markers with the severity of specific behavioral traits as scored by Childhood Autism Rating Scale (CARS) has been examined as quantitative trait (QT) analysis using IBM-SPSS program. A total of 225 ASD patients (190 male and 35 female) were recruited after psychometric evaluation done by DSM-IV-TR/DSM-5 criteria and assessment by CARS. Genotyping carried by PCR/RFLP/sequencing methods, and population were found in Hardy-Weinberg equilibrium. The outcome of the QT analysis indicating the increased score in overall CARS were associated with G and C allele of MAOB marker rs3027449 (p-value: 0.03) and rs1040399 (p-value: 0.01), respectively in male ASD children. In addition to this, major alleles of studied polymorphisms of gene were found to be statistically associated with the higher impairment in social communication domain only in male ASD children. Overall outcome of the study suggests likely involvement of MAOB with ASD in a gender-specific manner with the severity in behavior phenotypes. Considering the cumulative impact of these markers in regulating the severity of the behavioral symptoms of ASD, it is likely that MAOB gene is associated with the disorder.

Presence of platelet hyperserotonemia and effective amelioration of behavioral dysfunctions by selective serotonin reuptake inhibitors (SSRI) in autism spectrum disorders (ASD) indicate that irregularities in serotonin (5-HT) reuptake and its homeostasis could be the basis of behavioral impairments in ASD patients. SLC6A4, the gene encoding serotonin transporter (SERT) is considered as a potential susceptibility gene for ASD, since it is a quantitative trait locus for blood 5-HT levels. Three functional polymorphisms, 5-HTTLPR, STin2 and 3'UTR-SNP of SLC6A4 are extensively studied for possible association with the disorder, with inconclusive outcome. In the present study, we investigated association of these polymorphisms with platelet 5-HT content and symptoms severity as revealed by childhood autism rating scale in ASD children from an Indian population. Higher 5-HT level observed in ASD was highly significant in children with heterozygous and homozygous genotypes comprising of minor alleles of the markers. Quantitative transmission disequilibrium test demonstrated significant genetic effect of STin2 allele as well as STin2/3'UTR-SNP and 5-HTTLPR/3'UTR-SNP haplotypes on 5-HT levels, but no direct association with overall CARS score and ASD phenotype. Significant genetic effect of the markers on specific behavioral phenotypes was observed for various sub-phenotypes of CARS in quantitative trait analysis. Even though the 5-HT level was not associated with severity of behavioral CARS score, a significant negative relationship was observed for 5-HT levels and level and consistency of intellectual response and general impression in ASD children. Population-based study revealed higher distribution of the haplotype 10/G of STin2/3'UTR-SNP in male controls, suggesting protective effect of this haplotype in male cases. Overall results of the study suggest that SLC6A4 markers have specific genetic effect on individual ASD behavioral attributes, might be through the modulation of 5-HT content.

Huntington's disease (HD) is an autosomal dominant disease, with overt movement dysfunctions. Despite focused research on the basis of neurodegeneration in HD for last few decades, the mechanism for the site-specific lesion of neurons in the brain is not clear. All the explanations that partially clarify the phenomenon of neurodegeneration leads to one organelle, mitochondrion, which is severely affected in HD at the level of electron transport chain, Ca(2+) buffering efficiency and morphology. But, with the existing knowledge, it is not clear whether the cell death processes in HD initiate from mitochondria, though the Huntingtin (Htt) aggregates show close proximity to this organelle, or do some extracellular stimuli like TNFα or FasL trigger the process. Mainly because of the disparity in the different available experimental models, the results are quite confusing or at least inconsistent to a great extent. The fact remains that the mutant Htt protein was seen to be associated with mitochondria directly, and as the striatum is highly enriched with dopamine and glutamate, it may make the striatal mitochondria more vulnerable because of the presence of dopa-quinones, and due to an imbalance in Ca(2+). The current therapeutic strategies are based on symptomatic relief, and, therefore, mainly target neurotransmitter(s) and their receptors to modulate behavioral outputs, but none of them targets mitochondria or try to address the basic molecular events that cause neurons to die in discrete regions of the brain, which could probably be resulting from grave mitochondrial dysfunctions. Therefore, targeting mitochondria for their protection, while addressing symptomatic recovery, holds a great potential to tone down the progression of the disease, and to provide better relief to the patients and caretakers.