An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol.
- Authors
- Lasek, Amy W; Lim, Jana; Kliethermes, Christopher L; Berger, Karen H; Joslyn, Geoff; Brush, Gerry; Xue, Liquan; Robertson, Margaret; Moore, Monica S; Vranizan, Karen; Morris, Stephan W; Schuckit, Marc A; White, Raymond L; Heberlein, Ulrike
- Year
- 2011
- Journal
- PloS one
- PMID
- 21799923
- DOI
- 10.1371/journal.pone.0022636
- PMCID
- PMC3142173
Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention.
dLmo regulates expression of dAlk.(A) Microarray analysis of dLmo gain-of-function (BxJ), loss-of-function (EP1306), and control flies (Ctl, w;iso). Three samples of RNA from fly heads of each genotype were hybridized to Affymetrix Drosophila 2.0 oligonucleotide microarray chips and subjected to HOPACH clustering after data processing and normalization. Shown is cluster 3, containing 43 genes showing an increase in dLmo gain-of-function and decrease in loss-of-function mutants. The position of dAlk in the cluster is indicated by an arrow. Green color indicates decreased expression and red increased expression (fold change) compared to the control. dAlk expression changes were significant by ANOVA (P = 0.015) (B) qPCR showing an 18% increase in dAlk expression in flies carrying the EP1306 allele. Total RNA was isolated from whole flies and cDNA synthesized for analysis by PCR. Expression of the dAlk transcript was normalized to the control transcript Rpl-32. (C) Increased ALK protein expression in EP1306 fly heads compared to control fly heads (Ctl) by western blotting. ImageJ quantification of the blots and normalization to α-tubulin protein levels indicated an overall 20% increase in ALK in EP1306 fly heads. (D) qPCR indicating increased dAlk expression in dLmo loss-of-function mutant flies Hdp and Pdrm. *P = 0.05 by ANOVA, n = 6–7 independent biological replicates.
LLM interpretation
This figure consists of four panels analyzing the regulation of *dAlk* by *dLmo*. Panel A is a heatmap showing a cluster of 43 genes, where *dAlk* (indicated by an arrow) shows increased expression (red) in *EP1306* mutants and decreased expression (green) in *BxJ* mutants compared to control (*Ctl*). Panels B and D are bar charts showing increased *dAlk* mRNA expression (normalized to *Rpl-32*) in *EP1306*, *Hdp*, and *Pdrm* mutants, with panel D indicating statistical significance (*P = 0.05). Panel C shows a western blot and corresponding bands for ALK and Tubulin, indicating higher ALK protein levels in *EP1306* fly heads compared to controls.
Insertions in dAlk affect ethanol sedation in flies.(A) Schematic of the Alk gene, showing the position of the f01491 and MB06458 P-element insertions. The boxes represent exons and connecting lines indicate introns. Shaded boxes illustrate the protein coding region. Arrow shows the direction of transcription. (B) Western blot showing reduced expression of dALK protein in heterozygous flies carrying the f01491 insertion. Blot was stripped and probed with antibody to α-tubulin to demonstrate equal loading of total protein. (C, D) Ethanol sedation curves and ST50 graphs (inset) of flies carrying the f01491 (C) and MB06458 (D) insertions, illustrating increased resistance of dAlk mutant flies to ethanol-induced sedation. Error bars, SEM, n = 8. P = 0.002 (f01491) and P = 0.008 (MB06458), ANOVA. (E) Ethanol sedation curves of flies carrying the f01491 insertion and elav-GAL4c155, showing rescue of f01491 ethanol sedation resistance phenotype by re-expressing dAlk in neurons of the mutant. (F) ST50 values for the ethanol sedation curves in (E). *P = 0.0018 by ANOVA.
LLM interpretation
This figure consists of a gene schematic (A), a Western blot (B), and several line and bar graphs (C-F) analyzing the effect of *dAlk* insertions on ethanol sedation in flies. The Western blot shows reduced ALK protein expression in *f01491/+* flies compared to control, while sedation curves and ST50 insets (C, D) show that *f01491* and *MB06458* insertions increase resistance to ethanol (P=0.002 and P=0.008, respectively). Finally, the sedation curve (E) and ST50 bar graph (F) demonstrate that re-expressing *dAlk* in neurons rescues the resistance phenotype of *f01491* flies (*P=0.0018).
Putative regulation of ethanol-related behaviors and brain Alk expression by the Alk locus.(A) Heat map of mouse chromosome 17 (right panel) depicting correlations between ethanol-related traits (lanes 1–3), Alk expression in specific brain regions (lanes 4–10) and genotype at the Alk locus (lane 11). Legend for the heat map is shown on the left. Blue indicates that the C57BL/6J genotype at the locus is associated with increased expression of the trait, red indicates the same for DBA/2J genotype, and increased likelihood ratio statistic (LRS) is indicated by darker color. The red region surrounding the marker rs4137129 in the Alk locus (lane 11) is arbitrarily colored and indicates the extent of linkage disequilibrium. (B) Scatter plot depicting the correlation between Alk expression in the striatum and ethanol intake. Lower Alk expression was associated with increased ethanol intake. (C) Scatter plot depicting the correlation between hippocampal Alk expression and the latency to fall in seconds as a measure of ethanol-induced ataxia using the screen test. Lower Alk expression was correlated with increased latency to fall.
LLM interpretation
This figure consists of a heat map and two scatter plots analyzing the relationship between the *Alk* locus, brain expression, and ethanol-related behaviors. (A) A heat map of mouse chromosome 17 shows correlations between ethanol traits (lanes 1–3), *Alk* expression in various brain regions (lanes 4–10), and genotype at the *Alk* locus (lane 11), with color indicating the associated genotype (blue for C57BL/6J, red for DBA/2J) and intensity representing the likelihood ratio statistic (LRS). (B) A scatter plot shows a negative correlation ($r = -0.8$) between *Alk* expression in the striatum and ethanol intake. (C) A scatter plot shows a negative correlation ($r = -0.51$) between *Alk* expression in the hippocampus and the latency to fall during an ethanol-induced ataxia test.
AlkKO mice show increased sedation in response to ethanol.(A) Western blot indicating loss of full-length ALK protein in the striatum of AlkKO mice (−/−) compared to heterozygous AlkKO (+/−) and wild-type (+/+) mice. Blot was stripped and probed with antibody to GAPDH to indicate equal protein loading. (B) LORR in AlkKO and wild-type mice at 3.6 and 4.0 g/kg ethanol. Shown is the time to recovery from sedation. *3.6 g/kg, F1,24 = 10.54, P = 0.003; *4.0 g/kg, F1,28 = 8.98, P = 0.006. (C) Blood ethanol concentration in AlkKO mice after an injection of 4.0 g/kg ethanol indicating no difference compared to wild-type controls. Shown is the blood ethanol concentration (BEC) in mg% over time. Error bars, SEM.
LLM interpretation
This figure consists of three panels: (A) a Western blot showing the absence of ALK protein in AlkKO (-/-) mice compared to heterozygous (+/-) and wild-type (+/+) mice, with GAPDH as a loading control. (B) A bar chart showing that AlkKO (-/-) mice have a significantly longer time to recovery from sedation compared to wild-type (+/+) mice at both 3.6 and 4.0 g/kg ethanol doses (*p < 0.01). (C) A line graph showing no significant difference in blood ethanol concentration (BEC) over 180 minutes between wild-type and AlkKO mice following a 4.0 g/kg ethanol injection.
Increased ethanol consumption in AlkKO mice.(A) Ethanol consumption in wild-type (+/+) and homozygous mutant (−/−) AlkKO mice, expressed in g/kg over a 4-hour period for 8 drinking sessions in the dark. There was a significant effect of genotype (genotype: F1,119 = 7.71, P = 0.013; session:F7,119 = 10.19, P<0.001; genotype by session interaction: F7,119 = 1.12, P = 0.356). (B) Blood ethanol concentration (BEC, mg%) in wild-type and homozygous AlkKO mice after the final drinking in the dark session, indicating increased BEC in AlkKO mice. *P = 0.02. (C) Water consumption, expressed in g/kg over a 4-hour period for one drinking session in the dark, indicating no effect of genotype on general fluid intake. Error bars, SEM.
LLM interpretation
This figure consists of one line graph and two bar charts comparing wild-type (+/+) and AlkKO (−/−) mice. Panel A shows that AlkKO mice consumed significantly more ethanol (g/kg) across eight drinking sessions compared to wild-type mice. Panel B shows a significantly higher blood ethanol concentration (BEC, mg%) in AlkKO mice (*P = 0.02), while Panel C shows no significant difference in water consumption (g/kg) between the two genotypes.
Effect of ALK genotype at rs17007646 on behavioral responses to alcohol in human subjects.(A) Body sway in the lateral direction (BSL) in cm/min as a function of genotype, indicating decreased BSL in response to alcohol in heterozygous individuals and individuals homozygous for the minor allele. (B) Subjective High Assessment Scale (SHAS) score in response to an alcohol challenge as a function of genotype. Individuals homozygous for the minor allele report a lower SHAS score. Shown are the group means. Error bars, SEM. Hom1, subjects homozygous for the major allele; Het, heterozygous subjects; Hom2, subjects homozygous for the minor allele.
LLM interpretation
This figure consists of two dot plots with error bars (SEM) showing the effect of ALK genotype (Hom1, Het, Hom2) on alcohol responses. Panel A shows a decrease in lateral body sway (BSL, cm/min) as the genotype moves from homozygous major (Hom1) to homozygous minor (Hom2). Panel B shows a similar downward trend in Subjective High Assessment Scale (SHAS) scores across the same genotype groups.
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