The human dopamine transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk synthesis, we have concluded that SLC6A3 represents an increasingly recognized risk with a growing number of familial mutants associated with neuropsychiatric and neurological disorders. At least five loci were related to common and severe diseases including alcohol use disorder (high activity variant), attention-deficit/hyperactivity disorder (low activity variant), autism (familial proteins with mutated networking) and movement disorders (both regulatory variants and familial mutations). Association signals depended on genetic markers used as well as ethnicity examined. Strong haplotype selection and gene-wide epistases support multimarker assessment of functional variations and phenotype associations. Inclusion of its promoter region's functional markers such as DNPi (rs67175440) and 5'VNTR (rs70957367) may help delineate condensate-based risk action, testing a locus-pathway-phenotype hypothesis for one gene-multidisease etiology.

• MeSH
• fenotyp MeSH
• haplotypy MeSH
• hyperkinetická porucha * genetika   MeSH
• lidé MeSH
• mutace MeSH
• proteiny přenášející dopamin přes plazmatickou membránu * genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Slow neurotransmission including DARPP-32 signalling is implicated in substance use disorders (SUDs) by experimental systems but not yet in the human aetiology. PPP1R12B, encoding another protein in the DARPP-32 family, hasn't been studied in the brain. METHODS: Brain-regional gene activity was assessed in three different animal models of SUDs for mRNA level alterations. Genetic associations were assessed by meta-analysis of pre-existing dbGaP GWAS datasets for main effects and epistasis with known genetic risks, followed by cell type-specific pathway delineation. Parkinson's disease (PD) was included as a dopamine-related disease control for SUDs. FINDINGS: In animal models of SUDs, environmentally-altered PPP1R12B expression sex-dependently involves motivation-related brain regions. In humans with polysubstance abuse, meta-analysis of pre-existing datasets revealed that PPP1R12B and PPP1R1B, although expressed in dopamine vs. dopamine-recipient neurons, exerted similar interactions with known genetic risks such as ACTR1B and DRD2 in men but with ADH1B, HGFAC and DRD3 in women. These interactions reached genome-wide significances (Pmeta<10-20) for SUDs but not for PD (disease selectivity: P = 4.8 × 10-142, OR = 6.7 for PPP1R12B; P = 8.0 × 10-8, OR = 2.1 for PPP1R1B). CADM2 was the common risk in the molecular signalling regardless of gender and cell type. INTERPRETATION: Gender-dependant slow neurotransmission may convey both genetic and environmental vulnerabilities selectively to SUDs. FUNDING: Grants from National Institute on Drug Abuse (NIDA) and National Institute on Alcohol Abuse and Alcoholism (NIAAA) of U.S.A. and National Natural Science Foundation of China (NSFC).

• MeSH
• celogenomová asociační studie MeSH
• dopaminem a cAMP regulovaný fosfoprotein 32 genetika   metabolismus   MeSH
• genetická epistáze * MeSH
• genetická heterogenita MeSH
• genetická predispozice k nemoci MeSH
• genové regulační sítě MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mozek metabolismus   patologie   MeSH
• myši MeSH
• náchylnost k nemoci MeSH
• nervový přenos genetika   MeSH
• orgánová specificita genetika   MeSH
• poruchy spojené s užíváním psychoaktivních látek diagnóza   etiologie   metabolismus   MeSH
• proteinfosfatasa 1 genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• sexuální faktory MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Playing an important role in the etiology of substance use disorder (SUD), dopamine (DA) neurons are subject to various regulations but transcriptional regulations are largely understudied. For the first time, we report here that the Human Immunodeficiency Virus Type I Enhancer Binding Protein 2 (HIVEP2) is a dopaminergic transcriptional regulator. HIVEP2 is expressed in both the cytoplasm and nuclei of DA neurons. Therein, HIVEP2 can target the intronic sequence GTGGCTTTCT of SLC6A3 and thereby activate the gene. In naive rats from the bi-directional selectively bred substance-preferring P vs -nonpreferring NP rat model of substance abuse vulnerability, increased gene activity in males was associated with the vulnerability, whereas decreased gene activity in the females was associated with the same vulnerability. In clinical subjects, extensive and significant HIVEP2-SLC6A3 interactions were observed for SUD. Collectively, HIVEP2-mediated transcriptional mechanisms are implicated in dopaminergic pathophysiology of SUD.

• MeSH
• buněčné jádro metabolismus   MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• dopaminergní neurony metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• poruchy spojené s užíváním psychoaktivních látek etiologie   genetika   MeSH
• proteiny přenášející dopamin přes plazmatickou membránu genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• sexuální faktory MeSH
• transkripční faktory genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

A promoter can be regulated by various cis-acting elements so that delineation of the regulatory modes among them may help understand developmental, environmental and genetic mechanisms in gene activity. Here we report that the human dopamine transporter gene SLC6A3 carries a 5' distal 5-kb super enhancer (5KSE) which upregulated the promoter by 5-fold. Interestingly, 5KSE is able to prevent 3' downstream variable number tandem repeats (3'VNTRs) from silencing the promoter. This new enhancer consists of a 5'VNTR and three repetitive sub-elements that are conserved in primates. Two of 5KSE's sub-elements, E-9.7 and E-8.7, upregulate the promoter, but only the later could continue doing so in the presence of 3'VNTRs. Finally, E-8.7 is activated by novel dopaminergic transcription factors including SRP54 and Nfe2l1. Together, these results reveal a multimodal regulatory mechanism in SLC6A3.

• MeSH
• biologické modely MeSH
• dospělí MeSH
• genetická transkripce * MeSH
• haplotypy genetika   MeSH
• lidé MeSH
• minisatelitní repetice genetika   MeSH
• myši inbrední C57BL MeSH
• nádorové buněčné linie MeSH
• promotorové oblasti (genetika) * MeSH
• proteiny přenášející dopamin přes plazmatickou membránu genetika   MeSH
• transkripční faktory metabolismus   MeSH
• zesilovače transkripce MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: It is established that natural medicines for Parkinson's disease (PD) provide an antioxidant activity in preventing dopaminergic neurons from degeneration. However, the underlying and related molecular details remain poorly understood. METHODS AND AIM: We review published in vitro and rodent studies of natural products in PD models with the aim to identify common molecular pathways contributing to the treatment efficacy. Commonly regulated genes were identified through the systemic literature search and further analyzed from a network perspective. FINDINGS: Approximately thirty different types of natural products have been investigated for their ability to regulate protein density and gene activity in various experimental systems. Most were found to attenuate neurotoxin-induced regulations. Three common PD pathways are involved. The most studied pathway was neuronal development/anti-apoptosis consisting of Bax/Bcl-2, caspases 3/9, and MAPK signaling. Another well studied was anti-inflammation comprising iNOS, nNOS, Nrf2/ARE, cytokines, TNFα, COX2 and MAPK signaling. The third pathway referred to dopamine transmission modulation with upregulated VMAT2, DAT, NURR1 and GDNF levels. To date, HIPK2, a conserved serine/threonine kinase and transcriptional target of Nrf2 in an anti-apoptosis signaling pathway, is the first protein identified as the direct binding target of a natural product (ZMHC). IMPLICATIONS: Natural products may utilize multiple and intercellular pathways at various steps to prevent DA neurons from degeneration. Molecular delineation of the mechanisms of actions is revealing new, perhaps combinational therapeutic approaches to stop the progression of DA degeneration.

• MeSH
• antiflogistika chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• biologické přípravky chemie   farmakologie   MeSH
• dopamin metabolismus   MeSH
• dopaminergní neurony účinky léků   metabolismus   MeSH
• lidé MeSH
• myši MeSH
• nervový přenos účinky léků   MeSH
• Parkinsonova nemoc farmakoterapie   MeSH
• signální transdukce účinky léků   MeSH
• zánět farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH