Content uploaded by Yingwei Mao
Author content
All content in this area was uploaded by Yingwei Mao on Sep 10, 2014
Content may be subject to copyright.
A preview of the PDF is not available
The Applications of Pharmacogenomics to Neurological Disorders
Abstract
The most common neurological disorders, including neurodegenerative diseases and psychiatric disorders, have received recent attention with regards to pharmacogenomics and personalized medicine. Here, we will focus on a neglected neurodegenerative disorder, cerebral ischemic stroke (CIS), and highlight recent advances in two disorders, Parkinson's disease (PD) and Alzheimer's diseases (AD), that possess both similar and distinct mechanisms in regards to therapeutic targets. Current attempts to link symptoms from other disorders to candidate genes have been effective in identifying candidate genes for stroke [1, 2], AD [3], and PD [4, 5]. In the first part of this review, we will focus primarily on mechanisms that are somewhat specific to each disorder which are significantly involved in neurodegeneration (i.e., protease pathways, calcium homeostasis, reactive oxygen species regulation, DNA repair mechanisms, neurogenesis regulation, mitochondrial function, etc.). In the second part of this review, we will discuss the applications of the genome-wide technology on pharmacogenomics of mental illnesses including schizophrenia (SCZ), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD).
... It is linked with our present study. The previous study suggests that the HSPG2 factor is associated with Alzheimer's disease, although its function in ASD is still unclear [82]. Table 6 represents only those biomarkers that were associated with previous ASD-related literature as well as associated with our current study. ...
Autism spectrum disorder (ASD) is a collection of neurological disabilities marked by difficulties with behavior, speech, language, and interaction. It is a complicated and behaviorally defined static disorder of the developing brain. Recently it has become a serious concern across the world. The goal of this project was to use bioinformatics tools and network biology to uncover the molecular signatures and pathways of ASD. We investigated brain transcriptomics gene expression datasets and determined 47 dysregulated differentially expressed common genes. Several kinds of crucial neurodegeneration-related molecular mechanisms in the signaling structures were determined as a result of these investigations. We implemented gene set enrichment analysis (GSEA) using bimolecular pathways and gene ontology (GO) terms to determine the role of these differentially expressed genes (DEGs), as well as protein-protein interactions (PPI), transcriptional factor interactions, and post-transcriptional factor interactions. PPI network collected the top ten hub genes including KIT, PIN1, GATA1, GRIN2A, PBX2, BLK, ATP6V1B1, TCF7L1, TRAF1, and HSPG2. The PPI network also revealed the existence of two sub-networks. Moreover, several transcription factors (NFIC, USF2, TFAP2A, RELA, FOXL1, GATA2, YY1, FOXC1, NFKB1, and E2F1) and post-transcription factors (mir-335-5p, mir-26b-5p, mir-124-3p, mir-192-5p, mir-1-3p, mir-215-5p, mir-6825-5p, mir-146a-5p, mir-8485, and mir-93-5p) were found throughout this study. Some drug-like molecules were also predicted that might have a beneficial effect against ASD. We detected potentially novel links between pathogenic conditions in ASD patient's brain tissues. This work offers molecular biomarkers at the gene expression level and protein bases that could aid in a better understanding of molecular pathways, as well as potential pharmacological approaches and therapies for developing effective ASD treatments.
... On the other hand, mRNA levels of SUMO1, Ubc9 and SENP1 were decreased in murine brain tissues with age [36]. Recently, age-associated changes of sumoylation were highlighted in studies of Alzheimer's disease (AD), one of the most common and debilitating neurodegenerative disease in the elderly, and currently it is difficult to be pharmaceutically targeted [37][38][39][40][41][42]. Sumoylation was found to be critically modulating AD-associated key proteins, such as tau and amyloid β precursor proteins [43,44]. ...
Sumoylation is a reversible post-translational modification that conjugates small peptide SUMO (small ubiquitin-like modifier) to a target protein. Global protein sumoylation and expression of components in sumoylation pathway were recently found to be altered in the process of organismal aging. In addition, key factors controlling cellular senescence are known to be sumoylated. This review will summarize current information on the function of sumoylation in cellular senescence and aging.
Neurological disorders include diverse subgroups, including neuromuscular diseases, genetic and metabolic disorders, developmental delay, traumatic brain disorders and injuries, and degenerative diseases. Polypharmacological treatment of neurological disorders is getting popular and, on some occasions, has become the mainstay therapeutic strategy. This chapter introduces the basic knowledge of polypharmacology-based therapeutic approaches for neurological disorders, as well as new multitarget drugs under development for the treatment of neurological disorders. Focus is given to CDT, FDC, and MTD approaches for the treatment of Alzheimer’s disease, Parkinson’s disease, epilepsy, multiple sclerosis, and schizophrenia, which represent some of the most difficult and challenging neurological disorders.KeywordsNeurological polypharmacologyAlzheimer’s diseaseParkinson’s diseaseSchizophreniaMultitarget therapy
Kainate receptors (KARs) are glutamate receptors that participate in the postsynaptic transmission of information and in the control of neuronal excitability, as well as presynaptically modulating the release of the neurotransmitters GABA and glutamate. These modulatory effects, general follow a biphasic pattern, with low KA concentrations provoking an increase in GABA and glutamate release, and higher concentrations mediating a decrease in the release of these neurotransmitters. In addition, KARs are involved in different forms of long‐ and short‐term plasticity. Importantly, altered activity of these receptors has been implicated in different central nervous system diseases and disturbances. Here, we describe the pre‐ and postsynaptic actions of KARs, and the possible role of these receptors in disease, a field that has seen significant progress in recent years.
Abstract Parkinson's disease (PD) is a debilitating, demoralizing and financially devastating condition affecting 1% of population at the age of 60 years. Thus, very important issue to address is individual therapy optimization. Recent results have shown evidence that variable efficacy of treatment and risk of motor and mental complications could have genetic origin. Significant roles in that process play (pharmaco)genomic/genetic studies of PD. Variability in genes coding for drug-metabolizing enzymes, drug receptors and proteins involved in drug pathway signaling is an important factor determining inter-individual variability in drug responses. Interpersonal differences in drug responses are clearly documented although individualized treatment of PD is not widely known. Treatment with antiparkinsonian drugs is associated with the development of complications, such as L-DOPA-induced dyskinesia (LID), hallucinations and excessive daytime sleepiness. Carriers of specific genetic polymorphisms are particularly susceptible to development of some of these drug adverse effects. Pharmacogenomics aims to understand the relationship between genetic factors and inter-individual variations in drug responses, and to translate this information in therapy tailored to individual patient genetics. Relatively few efforts have been made to investigate the role of pharmacogenetics in the individual response to anti-PD drugs. Thus, many genetic variations and polymorphisms in myriad of different proteins can influence individual response to anti-PD drugs.
Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity(1,2). We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk(3). Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.
Background Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. Methods We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. Results We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1×10?7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies.
Genetic factors could have a role in determining the occurrence of levodopa-induced peak-dose dyskinesias in Parkinson's disease (PD), since a substantial proportion of patients never develop peak-dose dyskinesias. To investigate whether an intronic short-tandem repeat (STR) polymorphism in the gene for the dopamine receptor D2 (DRD2) is associated with the risk of developing peak-dose dyskinesias in PD, we performed a case-control study of 136 subjects with sporadic PD and 224 population control subjects. The 15 allele of the STR polymorphism of the DRD2 gene was more frequent in parkinsonian subjects than in controls. Moreover, the frequency of both alleles 13 and 14 was higher in nondyskinetic than in dyskinetic PD subjects. The risk reduction of developing peak-dose dyskinesias for PD subjects carrying at least one of the 13 or 14 alleles was 72% with respect to the PD subjects who did not carry these alleles. The present results indicate that certain alleles of the STR polymorphism of the DRD2 gene reduce the risk of developing peak-dose dyskinesias.
We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 x 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 x 10(-9)), ANK3 (rs10994359, P = 2.5 x 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 x 10(-9)).
The concept of neuroprotective therapy for acute ischemic stroke to salvage tissue at risk and improve functional outcome is based on sound scientific principles and extensive preclinical animal studies demonstrating efficacy. The failure of most neuroprotective drugs in clinical trials has been due to inadequate preclinical testing and flawed clinical development programs. The Stroke Therapy Academic Industry Roundtable (STAIR) group has outlined rational approaches to preclinical and clinical studies. The positive results from the first Stroke-Acute-Ischaemic-NXY-Treatment (SAINT-I) trial of the free-radical spin-trap drug, NXY-059, which followed many of the STAIR guidelines, reinvigorated enthusiasm in neuroprotection, but the SAINT-II trial did not replicate the positive effect on the same primary prespecified outcome measure. This has led to concerns about the future of neuroprotection as a therapeutic strategy for acute ischemic stroke. We discuss new suggestions to bridge the chasm between preclinical animal modeling and acute human stroke trials to potentially enhance the future assessment of novel neuroprotective drugs.
Ischaemic stroke can be caused by a number of monogenic disorders, and in such cases stroke is frequently part of a multisystem disorder. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the NOTCH: 3 gene, is increasingly appreciated as a cause of familial subcortical stroke. The genetics and phenotypes of monogenic stroke are covered in this review. However, the majority of cases of ischaemic stroke are multifactorial in aetiology. Strong evidence from epidemiological and animal studies has implicated genetic influences in the pathogenesis of multifactorial ischaemic stroke, but the identification of individual causative mutations remains problematic; this is in part limited by the number of approaches currently available. In addition, genetic influences are likely to be polygenic, and ischaemic stroke itself consists of a number of different phenotypes which may each have different genetic profiles. Almost all human studies to date have employed a candidate gene approach. Associations with polymorphisms in a variety of candidate genes have been investigated, including haemostatic genes, genes controlling homocysteine metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The results of these studies, and the advantages and limitations of the candidate gene approach, are presented. The recent biological revolution, spurred by the human genome project, promises the advent of novel technologies supported by bioinformatics resources that will transform the study of polygenic disorders such as stroke. Their potential application to polygenic ischaemic stroke is discussed.