Yanli Zhang-James

PGC-1α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease

Abnormal expression of genes for energy regulation in Parkinson’s disease patients identifies a master regulator as a possible therapeutic target for early intervention. Getting to the Root of Parkinson’s Disease Parkinson’s disease (PD) is a debilitating neurodegenerative disorder that results in the loss of dopamine neurons in the substantia nigra of the brain. Degeneration of these movement-related neurons predictably causes rigidity, slowness of movement, and resting tremor, but patients also show cognitive changes. Although gene mutations have been identified in several families with PD, the cause of the more common sporadic form is not known. Certain environmental factors, such as exposure to the pesticide rotenone, combined with a genetic susceptibility, are thought to confer risk for developing PD. A key pathological feature seen in postmortem brain tissue from PD patients is Lewy bodies, neuronal inclusions containing clumps of the α-synuclein protein (which is mutated in familial PD), as well as damaged mitochondria. Taking a systems biology approach to pinpoint the root cause of PD, Zheng et al. now implicate altered activity of the master transcription factor PGC-1α and the genes it regulates in the early stages of PD pathogenesis. To detect new sets of genes that may be associated with PD, the investigators did a meta-analysis of 17 independent genome-wide gene expression microarray studies that had been performed on a total of 322 postmortem brain tissue samples and 88 blood samples. The samples came from presymptomatic and symptomatic PD patients, as well as from control individuals who did not show any neurological deficits at autopsy. Nine genome-wide expression studies were conducted either on dopaminergic neurons obtained by laser capture from substantia nigra (three studies) or on substantia nigra homogenates (six studies). The authors then used a powerful tool called Gene Set Enrichment Analysis to sift through 522 gene sets (a gene set is a group of genes involved in one biological pathway or process). At the end of this tour-de-force analysis, they identified 10 gene sets that were all associated with PD. The gene sets with the strongest association contained nuclear genes encoding subunits of the electron transport chain proteins found in mitochondria. These genes all showed decreased expression in substantia nigra dopaminergic neurons (obtained by laser capture) even in the earliest stages of PD. Furthermore, a second gene set associated with PD and also underexpressed in the earliest stages of PD encodes enzymes involved in glucose metabolism. These results are compelling because many studies have already implicated dysfunctional mitochondria and altered energy metabolism as well as defective glucose metabolism in PD. The authors realized that these gene sets had in common the master transcriptional regulator, PGC-1α, and surmised that disruption of PGC-1α expression might be a root cause of PD. They tested this hypothesis in cultured dopaminergic neurons from embryonic rat midbrain forced to express a mutant form of α-synuclein. Overexpression of PGC-1α in these neurons resulted in activation of electron transport genes and protection against neuronal damage induced by mutant α-synuclein. In other cultured neurons treated with rotenone, overexpression of PGC-1α also was protective, blocking pesticide-induced neuronal cell death. These exciting findings identify altered expression of PGC-1α and the genes it regulates as key players during early PD pathogenesis. This potential new target could be exploited therapeutically to interfere with the pathological process during the earliest stages before permanent damage and neuronal loss occurs. Parkinson’s disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson’s and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson’s disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson’s disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson’s disease identifies PGC-1α as a potential therapeutic target for early intervention.

Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. Method: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. Results: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. Conclusions: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

Functional effects of dopamine transporter gene genotypes on in vivo dopamine transporter functioning: a meta-analysis.

Much psychiatric genetic research has focused on a 40-base pair variable number of tandem repeats (VNTR) polymorphism located in the 3′-untranslated region (3′UTR) of the dopamine active transporter (DAT) gene (SLC6A3). This variant produces two common alleles with 9- and 10-repeats (9R and 10R). Studies associating this variant with in vivo DAT activity in humans have had mixed results. We searched for studies using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) to evaluate this association. Random effects meta-analyses assessed the association of the 3′UTR variant with DAT activity. We also evaluated heterogeneity among studies and evidence for publication bias. We found twelve studies comprising 511 subjects, 125 from PET studies and 386 from SPECT studies. The PET studies provided highly significant evidence that the 9R allele was associated with increased DAT activity in human adults. The SPECT studies were highly heterogeneous. As a group, they suggested no association between the 3′UTR polymorphism and DAT activity. When the analysis was limited to the most commonly used ligand, [123I]β-CIT, stratification by affection status dramatically reduced heterogeneity and revealed a significant association of the 9R allele with increased DAT activity for healthy subjects. In humans, the 9R allele of the 3′UTR polymorphism of SLC6A3 regulates dopamine activity in the striatal brain regions independent of the presence of neuropsychiatric illness. Differences in study methodology account for the heterogeneous results across individual studies.

Oxidative Stress and ADHD: A Meta-Analysis

Objective: To clarify the role of oxidative stress and antioxidant activity in ADHD. Method: We examined the association of ADHD and oxidative stress by applying random effects meta-analysis to studies of oxidative stress and antioxidant status in medication naive patients with ADHD and controls. Results: Six studies of a total of 231 ADHD patients and 207 controls met our selection criteria. The association between ADHD and antioxidant status was not significant. We found a significant association between ADHD and oxidative stress that could not be accounted for by publication bias. The significant association lost significance after correcting for intrastudy clustering. No one observation accounted for the positive result. Conclusion: These results are preliminary given the small number of studies. They suggest that patients with ADHD have normal levels of antioxidant production, but that their response to oxidative stress is insufficient, leading to oxidative damage.

The comorbidity of ADHD and autism spectrum disorder

ADHD and autism spectrum disorder are common psychiatric comorbidities to each another. In addition, there is behavioral, biological and neuropsychological overlap between the two disorders. There are also several important differences between autism spectrum disorder and ADHD. Treatment strategies for the comorbid condition will also be reviewed. Future areas of research and clinical need will be discussed.

Behavioral and genetic evidence for a novel animal model of Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Subtype

BackgroundAccording to DSM-IV there are three subtypes of Attention-Deficit/Hyperactivity Disorder, namely: ADHD predominantly inattentive type (ADHD-PI), ADHD predominantly Hyperactive-Impulsive Type (ADHD-HI), and ADHD combined type (ADHD-C). These subtypes may represent distinct neurobehavioral disorders of childhood onset with separate etiologies. The diagnosis of ADHD is behaviorally based; therefore, investigations into its possible etiologies should be based in behavior. Animal models of ADHD demonstrate construct validity when they accurately reproduce elements of the etiology, biochemistry, symptoms, and treatment of the disorder. Spontaneously hypertensive rats (SHR) fulfill many of the validation criteria and compare well with clinical cases of ADHD-C. The present study describes a novel rat model of the predominantly inattentive subtype (ADHD-PI).MethodsADHD-like behavior was tested with a visual discrimination task measuring overactivity, impulsiveness and inattentiveness. Several strains with varied genetic background were needed to determine what constitutes a normal comparison. Five groups of rats were used: SHR/NCrl spontaneously hypertensive and WKY/NCrl Wistar/Kyoto rats from Charles River; SD/NTac Sprague Dawley and WH/HanTac Wistar rats from Taconic Europe; and WKY/NHsd Wistar/Kyoto rats from Harlan. DNA was analyzed to determine background differences in the strains by PCR genotyping of eight highly polymorphic microsatellite markers and 2625 single nucleotide polymorphisms (SNPs).ResultsCompared to appropriate comparison strains (WKY/NHsd and SD/NTac rats), SHR/NCrl showed ADHD-C-like behavior: striking overactivity and poor sustained attention. Compared to WKY/NHsd rats, WKY/NCrl rats showed inattention, but no overactivity or impulsiveness. WH/HanTac rats deviated significantly from the other control groups by being more active and less attentive than the WKY/NHsd and SD/NTac rats. We also found substantial genomic differences between the WKY/NCrl and WKY/NHsd rats for eight short tandem repeat loci and 2625 SNPs. About 33.5 percent of the genome differs between the two WKY rat substrains, with large stretches of divergence on each chromosome.DiscussionThese data provide solid behavioral and genetic evidence that the WKY/NCrl and WKY/NHsd rats should be considered as separate substrains. Moreover, the behavioral features of the WKY/NCrl rat indicate that it should be a useful model for ADHD-PI, the primarily inattentive subtype of ADHD. The SD/NTac and the WH/HanTac rats show significant genetic and/or behavioral differences from WKY/NHsd rats and appear not to be appropriate controls in studies using the SHR/NCrl. The present results support the conclusion that SHR/NCrl is the best validated animal model of ADHD-C. The overactivity, impulsiveness and deficient sustained attention of the SHR/NCrl strain are independent behaviors. Thus, overactivity does not account for this strains impulsiveness and deficient sustained attention. Finally, the present study shows that great care has to be exercised to select the model and comparison groups.

An update on the comorbidity of ADHD and ASD: a focus on clinical management

ABSTRACT Attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) commonly co-occur. With the DSM-5, clinicians are permitted to make an ASD diagnosis in the context of ADHD. In earlier versions of the DSM, this was not acceptable. Both ASD and ADHD are reported to have had substantial increases in prevalence within the past 10 years. As a function of both the increased prevalence of both disorders as well as the ability to make an ASD diagnosis in ADHD, there has been a significant amount of research focusing on the comorbidity between ADHD and ASD in the past few years. Here, we provide an update on the biological, cognitive and behavioral overlap/distinctiveness between the two neurodevelopmental disorders with a focus on data published in the last four years. Treatment strategies for the comorbid condition as well as future areas of research and clinical need are discussed.

SLC9A9 mutations, gene expression, and protein–protein interactions in rat models of attention-deficit/hyperactivity disorder†‡

SLC9A9 (solute carrier family 9, member 9, also known as Na+/H+ exchanger member (NHE9)) is a membrane protein that regulates the luminal pH of the recycling endosome, an essential organelle for synaptic transmission and plasticity. SLC9A9 has been implicated in human attention deficit hyperactivity disorder (ADHD) and in rat studies of hyperactivity. We examined the SLC9A9 gene sequence and expression profile in prefrontal cortex, dorsal striatum and hippocampus in two genetic rat models of ADHD. We report two mutations in a rat model of inattentive ADHD, the WKY/NCrl rat, which affect the interaction of SLC9A9 with calcineurin homologous protein (CHP). We observed an age‐dependent abnormal expression of SLC9A9 in brains of this inattentive model and in the Spontaneous Hypertensive Rat (SHR) model of ADHD. Our data suggest a novel mechanism whereby SLC9A9 sequence variants and abnormalities in gene expression could contribute to the ADHD‐like symptoms of rat models and possibly the pathophysiology of ADHD in humans.

Genetic architecture of Wistar-Kyoto rat and spontaneously hypertensive rat substrains from different sources.

The spontaneously hypertensive rat (SHR) has been widely used as a model for studies of hypertension and attention deficit/hyperactivity disorder. The inbred Wistar-Kyoto (WKY) rat, derived from the same ancestral outbred Wistar rat as the SHR, are normotensive and have been used as the closest genetic control for the SHR, although the WKY has also been used as a model for depression. Notably, however, substantial behavioral and genetic differences among the WKY substrains, usually from the different vendors and breeders, have been observed. These differences have often been overlooked in prior studies, leading to inconsistent and even contradictory findings. The complicated breeding history of the SHR and WKY rats and the lack of a comprehensive understanding of the genetic background of different commercial substrains make the selection of control rats a daunting task, even for researchers who are mindful of their genetic heterogeneity. In this study, we examined the genetic relationship of 16 commonly used WKY and SHR rat substrains using genome-wide SNP genotyping data. Our results confirmed a large genetic divergence and complex relationships among the SHR and WKY substrains. This understanding, although incomplete without the genome sequence, provides useful guidance in selecting substrains and helps to interpret previous reports when the source of the animals was known. Moreover, we found two closely related, yet distinct WKY substrains that may provide novel opportunities in modeling psychiatric disorders.

Genetics of aggressive behavior: An overview.

The Research Domain Criteria (RDoC) address three types of aggression: frustrative non‐reward, defensive aggression and offensive/proactive aggression. This review sought to present the evidence for genetic underpinnings of aggression and to determine to what degree prior studies have examined phenotypes that fit into the RDoC framework. Although the constructs of defensive and offensive aggression have been widely used in the animal genetics literature, the human literature is mostly agnostic with regard to all the RDoC constructs. We know from twin studies that about half the variance in behavior may be explained by genetic risk factors. This is true for both dimensional, trait‐like, measures of aggression and categorical definitions of psychopathology. The non‐shared environment seems to have a moderate influence with the effects of shared environment being unclear. Human molecular genetic studies of aggression are in an early stage. The most promising candidates are in the dopaminergic and serotonergic systems along with hormonal regulators. Genome‐wide association studies have not yet achieved genome‐wide significance, but current samples are too small to detect variants having the small effects one would expect for a complex disorder. The strongest molecular evidence for a genetic basis for aggression comes from animal models comparing aggressive and non‐aggressive strains or documenting the effects of gene knockouts. Although we have learned much from these prior studies, future studies should improve the measurement of aggression by using a systematic method of measurement such as that proposed by the RDoC initiative.