Human Disease Model Report: alcohol, response to, learning and memory genes

General Information

Name

alcohol, response to, learning and memory genes

FlyBase ID

FBhh0000696

Disease Ontology Term

alcohol use disorder

Parent Disease

alcohol use disorder, susceptibility to (fly models overview)

OMIM

Overview

A large number of the genes involved in behavioral alcohol responses in flies, affecting ethanol sensitivity, ethanol tolerance or naive ethanol preference, are also implicated in learning and memory.

Early work identified learning mutations in amn and rut as also exhibiting changes in the normal response to alcohol; both of these genes are involved in cAMP signaling. In a screen of known learning mutations, 21 out 52 exhibited alterations in ethanol sensitivity and/or tolerance. See reviews Robinson and Atkinson, 2013 (FBrf0222263) and Park et al., 2017 (FBrf0235911).

Invoking a learning paradigm using Drosophila larvae, it has been shown that moderate ethanol consumption initially degrades the capacity of larvae to learn, but they eventually adapt and are able to learn as well as ethanol-naive animals. Withholding ethanol from ethanol-adapted larvae impairs learning. Ethanol reinstatement restores the capacity to learn, demonstrating cognitive dependence on ethanol.

[updated Jan. 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, learning and memory genes

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

External links

Disease synonyms

AUD susceptibility, learning and memory genes

Search term: alcohol use disorder

Related Diseases

Related human health report(s)

alcohol, response to, NPY-related

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

Other mammalian ortholog(s) used

D. melanogaster Gene Information (6)

Dmel\amn

Gene Snapshot

amnesiac (amn) encodes an apparent pre-pro-neuropeptide that functions to prolong medium-term memory. In the adult, it is almost entirely concentrated in two large neurosecretory cells (Dorsal Paired Median cells). [Date last reviewed: 2019-02-28]

Molecular function (GO)

neuropeptide hormone activity

Cellular component (GO)

extracellular space

Gene Groups / Pathways

NPPH

Comments on ortholog(s)

Orthologs and Alignments from DRSC

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

H. sapiens (Human)

Dmel\kra

Gene Snapshot

krasavietz (kra) encodes a translational regulator that is able to interact with the translation initiation factor encoded by eIF2β. It is involved in axon guidance, long-term memory, and alcohol addiction. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Orthologs and Alignments from DRSC

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

H. sapiens (Human)

Dmel\Adcy1

Gene Snapshot

Adenylate cyclase 1 (Adcy1) encodes a membrane-bound Ca[2+]/calmodulin-activated adenylyl cyclase that is responsible for synthesis of cAMP. It plays a key role in regulating behavioral, neuroanatomical, and electrophysiological plasticity. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Orthologs and Alignments from DRSC

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

H. sapiens (Human)

Dmel\sca

Gene Snapshot

scabrous (sca) encodes a secreted glycoprotein with partial homology to fibrinogen and its relatives. It is a transcriptional target of proneural bHLH proteins and a useful marker for proneural regions and cells. It contributes to neural patterning and interacts with the Notch pathway. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Orthologs and Alignments from DRSC

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

H. sapiens (Human)

Dmel\NPFR

Gene Snapshot

Contributions welcome

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Orthologs and Alignments from DRSC

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

H. sapiens (Human)

Dmel\Pde4

Gene Snapshot

Phosphodiesterase 4 (Pde4) encodes a cAMP-specific phosphodiesterase, responsible for cAMP degradation. Pde4 product plays a pivotal role in neurological and behavioral plasticity including synaptic development and function, learning and courtship. The product of Pde4 is also known to affect regulation of several developmental processes such as oogenesis. [Date last reviewed: 2019-03-21]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

CNPD

Comments on ortholog(s)

Moderate- to high-scoring ortholog of human PDE4B, PDE4D, PDE4A, PDE4C (1 Drosophila to 4 human). Dmel\dnc shares 46-58% identity and 57-72% similarity with the human genes.

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 (19 groups)

amn

RNA-protein

Interacting group

Assay

References

amn - orb2

pull down, western blot

(Mastushita-Sakai et al., 2010)

kra

protein-protein

Interacting group

Assay

References

kra - eIF2β

pull down, autoradiography, anti tag coimmunoprecipitation, anti tag western blot

(Lee et al., 2007)

kra - Gapdh1

anti bait coimmunoprecipitation, Identification by mass spectrometry

(Wang et al., 2006)

kra - Gapdh2

anti bait coimmunoprecipitation, Identification by mass spectrometry

(Wang et al., 2006)

kra - RpL5

pull down, western blot, anti bait coimmunoprecipitation, Identification by mass spectrometry, anti tag western blot

(Wang et al., 2006)

kra - RpL7A

anti bait coimmunoprecipitation, Identification by mass spectrometry

(Wang et al., 2006)

kra - RpS4

anti bait coimmunoprecipitation, Identification by mass spectrometry

(Wang et al., 2006)

kra - RpS8

anti bait coimmunoprecipitation, Identification by mass spectrometry

(Wang et al., 2006)

kra - RpS9

anti bait coimmunoprecipitation, Identification by mass spectrometry

(Wang et al., 2006)

kra - shot

pull down, autoradiography, anti tag coimmunoprecipitation, anti tag western blot, two hybrid

(Lee et al., 2007)

Adcy1

RNA-RNA

Interacting group

Assay

References

Adcy1 - mir-282

fluorescence technology, quantitative reverse transcription pcr

(Vilmos et al., 2013)

sca

protein-protein

Interacting group

Assay

References

sca - Delta

anti bait coimmunoprecipitation, western blot, affinity technology, fluorescence microscopy, coimmunoprecipitation, anti tag coimmunoprecipitation

(Petruccelli et al., 2018, Mok et al., 2005)

sca - N

anti tag coimmunoprecipitation, western blot

(Petruccelli et al., 2018)

RNA-protein

Interacting group

Assay

References

sca - Sxl

anti bait coimmunoprecipitation, quantitative reverse transcription pcr

(Sandler et al., 2018)

NPFR

protein-protein

Interacting group

Assay

References

NPFR - NPF

phenotype-based detection assay, fluorescence microscopy, inferred by author

(Johnson et al., 2003)

RNA-RNA

Interacting group

Assay

References

NPFR - mir-276a

luminiscence technology, western blot

(Zhang et al., 2021)

NPFR - mir-276b

luminiscence technology

(Zhang et al., 2021)

Pde4

RNA-protein

Interacting group

Assay

References

Pde4 - aub

iclip, partial RNA sequence identification

(Ma et al., 2017, Barckmann et al., 2015)

Pde4 - hang

pull down, quantitative reverse transcription pcr

(Ruppert et al., 2017)

Alleles Reported to Model Human Disease (Disease Ontology) (21 alleles)

amn

Models Based on Experimental Evidence ( 4 )

Allele

Disease

Evidence

References

amn¹

model of alcohol use disorder

CEA

(Larnerd et al., 2023, Moore et al., 1998)

amn^28A

model of alcohol use disorder

CEA

(Moore et al., 1998)

amn^X8

model of alcohol use disorder

CEA

(Moore et al., 1998)

amn^chpd

model of alcohol use disorder

CEA

(Moore et al., 1998)

Modifiers Based on Experimental Evidence ( 0 )

Allele

Disease

Interaction

References

kra

Models Based on Experimental Evidence ( 0 )

Allele

Disease

Evidence

References

Modifiers Based on Experimental Evidence ( 3 )

Allele

Disease

Interaction

References

kra^j9B6

exacerbates fragile X-associated tremor/ataxia syndrome

modeled by Zzzz\CGG^103.UAS.EGFP

(Singh et al., 2021)

kra^JF02556

exacerbates fragile X-associated tremor/ataxia syndrome

modeled by Zzzz\CGG^103.UAS.EGFP

(Singh et al., 2021)

kra^UAS.Tag:FLAG

ameliorates fragile X-associated tremor/ataxia syndrome

modeled by Zzzz\CGG^103.UAS.EGFP

(Singh et al., 2021)

Adcy1

Models Based on Experimental Evidence ( 3 )

Allele

Disease

Evidence

References

Adcy1^rut-1

model of alcohol use disorder

CEA

(Moore et al., 1998)

Adcy1^rut-2080

model of alcohol use disorder

CEA

(Moore et al., 1998)

Adcy1^MB769

model of alcohol use disorder

CEA

(Moore et al., 1998)

Modifiers Based on Experimental Evidence ( 4 )

Allele

Disease

Interaction

References

Adcy1^rut-1

exacerbates Parkinson's disease

modeled by Hsap\APP^{Aβ42.UAS.Tag:SS(rPENK)}

(Iijima-Ando et al., 2009)

exacerbates neurofibromatosis

modeled by Nf1^P2

(Tong et al., 2007)

ameliorates epilepsy

modeled by para^bss1

(Saras and Tanouye, 2016)

modeled by eas²

(Saras and Tanouye, 2016)

modeled by jus^iso7.8

(Saras and Tanouye, 2016)

Adcy1^rut-2080

exacerbates neurofibromatosis

modeled by Nf1^P2

(Tong et al., 2007)

Adcy1^JF02361

ameliorates fragile X syndrome

modeled by Hsap\FMR1^UAS.cSa

(Sears and Broadie, 2020)

Adcy1^UAS.cUa

ameliorates intellectual disability

modeled by chico¹

(Naganos et al., 2016)

sca

Models Based on Experimental Evidence ( 1 )

Allele

Disease

Evidence

References

sca^GD1965

model of alcohol use disorder

CEA

(Petruccelli et al., 2018)

Modifiers Based on Experimental Evidence ( 2 )

Allele

Disease

Interaction

References

sca^GD1965

ameliorates amyotrophic lateral sclerosis type 8

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

(Sanhueza et al., 2015)

sca^KK106319

ameliorates Alzheimer's disease 1

modeled by Hsap\APP^{Aβ42.UAS.cUa}

(Huang et al., 2024)

NPFR

Models Based on Experimental Evidence ( 1 )

Allele

Disease

Evidence

References

NPFR^RNAi.UAS

model of alcohol use disorder

CEA

(Shohat-Ophir et al., 2012)

Modifiers Based on Experimental Evidence ( 0 )

Allele

Disease

Interaction

References

Pde4

Models Based on Experimental Evidence ( 0 )

Allele

Disease

Evidence

References

Modifiers Based on Experimental Evidence ( 6 )

Allele

Disease

Interaction

References

Pde4^dnc-1

ameliorates fragile X syndrome

modeled by Fmr1³

(Kanellopoulos et al., 2012)

modeled by Fmr1^FS

(Choi et al., 2015)

ameliorates Parkinson's disease

modeled by Hsap\APP^{Aβ42.UAS.Tag:SS(rPENK)}

(Iijima-Ando et al., 2009)

ameliorates neurofibromatosis

modeled by Nf1^E2

(Walker et al., 2013)

Pde4^dnc-M14

ameliorates Huntington's disease

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

(Al-Ramahi et al., 2018)

ameliorates neurofibromatosis

modeled by Nf1^E2

(Walker et al., 2013)

Pde4^ML

ameliorates fragile X syndrome

modeled by Fmr1³

(Kanellopoulos et al., 2012)

ameliorates neurofibromatosis

modeled by Nf1^E2

(Walker et al., 2013)

Pde4^KK108541

ameliorates neurofibromatosis

modeled by Nf1^E2

(Walker et al., 2013)

Pde4^JF02561

ameliorates amyotrophic lateral sclerosis type 10

modeled by TBPH^N493D.UAS

(Ho et al., 2024)

modeled by TBPH^WT.UAS

(Ho et al., 2024)

Pde4^GL01226

ameliorates amyotrophic lateral sclerosis type 10

modeled by TBPH^N493D.UAS

(Ho et al., 2024)

modeled by TBPH^WT.UAS

(Ho et al., 2024)

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

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Pde4^GD5026

P{GD5026}

w¹¹¹⁸; P{GD5026}v15444

y¹ v¹; P{TRiP.JF02561}attP2

y¹ v¹; P{TRiP.GL01226}attP2/TM3, Sb¹

Pde4^HMC03573

P{TRiP.HMC03573}

y¹ sc^* v¹ sev²¹; P{TRiP.HMC03573}attP40

Pde4^RNAi.UAS.WIZ

P{UAS-Pde4.RNAi.WIZ}

w^*; P{UAS-Pde4.RNAi.WIZ}2

Adcy1^HMS06069

P{TRiP.HMS06069}

y¹ v¹; P{TRiP.HMS06069}attP40

Adcy1^GD3358

P{GD3358}

w¹¹¹⁸; P{GD3358}v5569

Adcy1^JF02361

P{TRiP.JF02361}

y¹ v¹; P{TRiP.JF02361}attP2/TM3, Sb¹

y¹ v¹; P{TRiP.JF01959}attP2

w¹¹¹⁸ P{GD1965}v44528

y¹ v¹; P{TRiP.JF03090}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.HMC04367}attP2

sca^HMJ30152

P{TRiP.HMJ30152}

y¹ v¹; P{TRiP.HMJ30152}attP40/CyO

amn^GD1178

P{GD1178}

w¹¹¹⁸; P{GD1178}v5606

amn^JF01814

P{TRiP.JF01814}

y¹ v¹; P{TRiP.JF01814}attP2

w¹¹¹⁸; P{GD8839}v25166

y¹ v¹; P{TRiP.JF02556}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.GL00690}attP2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Pde4^dnc-1

ethyl methanesulfonate

Pde4^dnc-1

Pde4^dnc-M14

amorphic allele - genetic evidence

ethyl methanesulfonate

y¹ Pde4^dnc-M14 cv¹ v¹ f¹/FM7a

Pde4^ML

amorphic allele - genetic evidence

ethyl methanesulfonate

Pde4^dnc-M11

amorphic allele - genetic evidence

ethyl methanesulfonate

Adcy1^rut-2080

Delta2-3 transposase

P{lArB}Adcy1^rut-2080; P{UAS-Adcy1.Z}2

Adcy1^MB769

Delta2-3 transposase

Adcy1^rut-1

loss of function allele

ethyl methanesulfonate

sc^e Adcy1^rut-1 f⁵ Sh¹⁴ / C(1)DX, y¹ f¹

Adcy1¹⁰⁴⁷

amorphic allele - molecular evidence

P-element activity

NPFR^lexA

amorphic allele - molecular evidence

CRISPR/Cas9

w¹¹¹⁸; TI{lexA::p65}NPFR^lexA

sca^8-1

loss of function allele

P-element activity

sca^73-1

loss of function allele

P-element activity

sca^BP1

amorphic allele - genetic evidence

PM hybrid dysgenesis

sca^88-3

amorphic allele - genetic evidence

ethyl methanesulfonate

sca^88-1

amorphic allele - genetic evidence

ethyl methanesulfonate

sca^KE3

amorphic allele - genetic evidence

ethyl methanesulfonate

sca^KX2

amorphic allele - genetic evidence

X ray

sca^BX1

amorphic allele - genetic evidence

X ray

sca^BP2

amorphic allele - genetic evidence

PM hybrid dysgenesis

cn¹ sca^BP2 bw¹/CyO

sca^BP3

amorphic allele - genetic evidence

PM hybrid dysgenesis

sca^OB7

loss of function allele

ethyl methanesulfonate

sca^OB7 / CyO

sca^88-2

amorphic allele - genetic evidence

ethyl methanesulfonate

sca^KE305

loss of function allele

ethyl methanesulfonate

sca^XL1

amorphic allele - genetic evidence

X ray

sca^KE15

amorphic allele - genetic evidence

ethyl methanesulfonate

sca¹

amorphic allele - genetic evidence

spontaneous

Adc^b-1 pr¹ cn¹ eve⁴ sca¹ / CyO, Duox^Cy dpy^lv1 pr¹ cn²

sca^KE17

amorphic allele - genetic evidence

ethyl methanesulfonate

amn^chpd

Delta2-3 transposase

P{PZ}amn^chpd; P{neoFRT.clipped}40A P{FRT(w^hs).clipped}G13; ry⁵⁰⁶

amn^EX

loss of function allele

Delta2-3 transposase

amn^28A

P-element activity

amn^X8

loss of function allele

Delta2-3 transposase

amn¹

loss of function allele

ethyl methanesulfonate

amn¹

kra^j9B6

P-element activity

y^d2 w¹¹¹⁸ P{ey-FLP.N}2 P{5xglBS-lacZ.38-1}TPN1; P{neoFRT}82B P{lacW}kra^j9B6/TM6B, P{Car20y}TPN1, Tb¹

References (19)

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