Human Disease Model Report: alcohol, response to, SIRT1-related

General Information

Name

alcohol, response to, SIRT1-related

FlyBase ID

FBhh0000909

Disease Ontology Term

alcohol use disorder

Parent Disease

alcohol use disorder, susceptibility to (fly models overview)

OMIM

Overview

This report describes characterization of the fly alcohol response using the Drosophila gene Sirt1. Dmel\Sirt1 encodes an NAD-dependent protein deacetylase that that functions during euchromatic and heterochromatic gene silencing and deacetylates a broad range of transcription factors and coregulators; it is orthologous to the human gene SIRT1. RNAi-targeting constructs, alleles caused by insertional mutagenesis, and an amorphic mutation generated by targeted recombination have been generated for Dmel\Sirt1.

The human SIRT1 gene has not been introduced into flies.

Animals homozygous for an amorphic alleles of Dmel\Sirt1 survive to adulthood, but exhibit multiple locomotor and behavioral phenotypes. Mutant flies exhibit unconditioned ethanol preference, are less sensitive to the sedating effects of acute ethanol exposure, and show a marked decrease in sedation tolerance. RNAi-mediated knockdown of Sirt1 in various tissues has demonstrated that Sirt1 is required in neurons, including in the brain, for normal development of ethanol tolerance, but not for normal ethanol sensitivity. Potential regulatory targets of Sirt1 in the context of alcohol response have been investigated.

Genetic and physical interactions of Dmel\Sirt1 have been described; see below and in the Sirt1 gene report.

[updated Oct. 2018 by FlyBase; FBrf0222196]

Disease Summary Information

Parent Disease Summary: alcohol use disorder, susceptibility to (fly models overview)

Symptoms and phenotype

Alcoholism can be defined as persistence of excessive drinking over a long period of time despite adverse health effects and disruption of social relations (Morozova et al., 2014; pubmed:24395673).

(FlyBase Curators, 2013-)

The 2013 Diagnostic and Statistical Manual of Mental Disorders (DSM) combined the two former categorizations of abnormal alcohol use (alcohol abuse and alcohol dependence) into one diagnosis: alcohol use disorder. The severity of an individual's AUD is broken into classifications: mild, moderate, or severe. "Alcoholism" is a non-medical term often used to describe a severe form of alcohol use disorder. (https://www.therecoveryvillage.com/recovery-blog/alcoholism-alcohol-use-disorder-whats-difference/)

(FlyBase Curators, 2013-)

Excessive alcohol consumption is associated with increased risk of different types of cancer, higher cardiovascular disease mortality, birth defects, liver diseases, and neuropsychiatric disorders (Morozova et al., 2014; pubmed:24395673).

(FlyBase Curators, 2013-)

Alcoholism is a multifactorial, genetically influenced disorder. [from MIM:103780; 2017.12.19]

(OMIM, 2013-)

Specific Disease Summary: alcohol, response to, SIRT1-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

SIRT1 belongs to the Silent information regulator (Sir2)-like family of deacetylases (also known as sirtuins), that deacetylate a broad range of transcription factors and coregulators. These NAD-dependent protein deacetylases link transcriptional regulation directly to intracellular energetics and participate in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metabolism, apoptosis and autophagy. [Gene Cards, SIRT1; 2018.10.23]

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): SIRT1
Gene Cards: SIRT1
MedlinePlus (gene): SIRT1
MARRVEL (human gene): SIRT1
NCBI (Entrez) gene: SIRT1; sirtuin 1

Disease synonyms

Search term: alcohol, response to, epigenetic mechanisms

Related Diseases

Related human health report(s)

alcohol use disorder, susceptibility to (fly models overview)

Related Specific Diseases

OMIM phenotypic series

Disease

Associated Human gene(s)

Drosophila model

Human transgene in Drosophila

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

SIRT1; sirtuin 1

D. melanogaster ortholog (based on DIOPT)

Dmel\Sirt1

(DIOPT, 2013-)

Comments on ortholog(s)

One to one: 1 human to 1 Drosophila.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Sirt1

Gene Snapshot

Sirtuin 1 (Sirt1) encodes an NAD⁺-dependent deacetylase that functions during euchromatic and heterochromatic gene silencing. Sirt1 product contributes to many biological pathways including neuronal function, apoptosis, metabolism, and development. [Date last reviewed: 2018-09-20]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

SIRT
NTCH-P

Comments on ortholog(s)

Moderate- to high-scoring ortholog of human SIRT1 (1 Drosophila to 1 human). Dmel\Sirt1 shares 39% identity and 51% similarity with the human gene.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (17 groups)

Sirt1

RNA-protein

Interacting group

Assay

References

Sirt1 - brat

anti tag coimmunoprecipitation, primer specific pcr

(Loedige et al., 2015)

protein-protein

Interacting group

Assay

References

Sirt1

enzymatic study, autoradiography

(Furuyama et al., 2004)

Sirt1 - Atg8a

pull down, anti tag western blot, anti tag coimmunoprecipitation

(Jacomin et al., 2020)

Sirt1 - Caf1-55

anti bait coimmunoprecipitation, western blot

(Furuyama et al., 2004)

Sirt1 - chinmo

anti tag coimmunoprecipitation, anti tag western blot

(Pandey et al., 2021)

Sirt1 - dpn

pull down, autoradiography

(Rosenberg and Parkhurst, 2002)

Sirt1 - E(z)

anti bait coimmunoprecipitation, western blot, pull down, autoradiography, molecular sieving

(Furuyama et al., 2004)

Sirt1 - FASN1

anti tag coimmunoprecipitation, anti tag western blot

(Miao et al., 2022)

Sirt1 - HDAC1

pull down, autoradiography, anti bait coimmunoprecipitation, western blot

(Furuyama et al., 2004)

Sirt1 - His4

enzymatic study, autoradiography

(Furuyama et al., 2004)

Sirt1 - Hnf4

anti tag coimmunoprecipitation, western blot

(Palu and Thummel, 2016)

Sirt1 - hry

pull down, autoradiography, anti tag western blot

(Rosenberg and Parkhurst, 2002)

Sirt1 - kis

anti bait coimmunoprecipitation, western blot, Identification by mass spectrometry

(Horvath et al., 2016)

Sirt1 - Nap1

anti bait coimmunoprecipitation, Identification by mass spectrometry, western blot

(Horvath et al., 2016)

Sirt1 - nej

anti bait coimmunoprecipitation, western blot, pull down, autoradiography

(Smolik, 2009)

Sirt1 - p53

anti tag coimmunoprecipitation, western blot

(Bauer et al., 2009)

Sirt1 - Su(H)

anti tag coimmunoprecipitation, anti tag western blot

(Horvath et al., 2016)

Alleles Reported to Model Human Disease (Disease Ontology) (8 alleles)

Sirt1

Models Based on Experimental Evidence ( 3 )

Allele

Disease

Evidence

References

Sirt1^2A-7-11

model of alcohol use disorder

CEA

(Larnerd et al., 2023, Kong et al., 2010)

Sirt1^4.5

model of type 2 diabetes mellitus

CEA with Sirt1^2A-7-11

(Palu and Thummel, 2016)

Sirt1^HMS00484

model of alcohol use disorder

CEA

(Larnerd et al., 2023)

Modifiers Based on Experimental Evidence ( 5 )

Allele

Disease

Interaction

References

Sirt1¹⁷

ameliorates Huntington's disease

modeled by Hsap\HTT^Q93.ex1.UAS

(Smith et al., 2014)

exacerbates Huntington's disease

modeled by Hsap\HTT^Q93.ex1.UAS

(Smith et al., 2014)

ameliorates neurodegenerative disease

modeled by Hsap\HTT^Q93.ex1.UAS

(Pallos et al., 2008)

Sirt1^EP2300

ameliorates Parkinson's disease

modeled by Pink1^B9

(Koh et al., 2012)

exacerbates autosomal dominant cerebellar ataxia

modeled by Hsap\ATXN1^82.UAS

(Ghosh and Feany, 2004)

modeled by Hsap\ATXN1^82Q.UAS

(Fernandez-Funez et al., 2000)

modeled by Hsap\ATXN1^30Q.UAS

(Fernandez-Funez et al., 2000)

exacerbates Huntington's disease

modeled by Hsap\HTT^{128Q.1-336.UAS}

(Branco et al., 2008)

exacerbates olivopontocerebellar atrophy

modeled by Hsap\ATXN1^82Q.UAS

(Branco et al., 2008)

ameliorates amyotrophic lateral sclerosis type 8

modeled by Vap33^{P58S.UAS.Tag:FLAG}

(Sanhueza et al., 2015)

Sirt1^UAS.cGa

ameliorates Parkinson's disease

modeled by Pink1^B9

(Koh et al., 2012)

Sirt1^UASp.Tag:MYC

ameliorates Barth syndrome

modeled by Taz⁸⁸⁹

(Damschroder et al., 2022)

Sirt1^UAS.cUa

ameliorates amyotrophic lateral sclerosis type 8

modeled by Vap33^{P58S.UAS.Tag:FLAG}

(Sanhueza et al., 2015)

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

w¹¹¹⁸; P{UASp-Sirt1.Myc}9c

Sirt1^UAS.cGa

P{UAS-Sirt1.G}

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

w¹¹¹⁸ P{GD11580}v23199

y¹ v¹; P{TRiP.JF01423}attP2

Sirt1^HMS00484

P{TRiP.HMS00484}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00484}attP2

y¹ v¹; P{TRiP.HMJ21708}attP40/CyO

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Sirt1^EP2300

P-element activity

w¹¹¹⁸; P{EP}Sirt1^EP2300 DnaJ-H^EP2300/CyO

Sirt1^4.5

Sirt1^4.5 cn¹/SM6b, P{eve-lacZ8.0}SB1

Sirt1¹⁷

Delta2-3 transposase

w¹¹¹⁸; Sirt1¹⁷/SM6a

Sirt1^2A-7-11

amorphic allele - molecular evidence

ends-in gene targeting

w¹¹¹⁸; Sirt1^2A-7-11

References (8)

Report Sections

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