2026-04-02 イェール大学
＜関連情報＞
- https://news.yale.edu/2026/04/02/zebrafish-reveal-new-insights-biology-autism
- https://www.pnas.org/doi/10.1073/pnas.2518846123
薬理行動プロファイリングにより、ゼブラフィッシュにおける自閉症関連遺伝子表現型の抑制因子が同定された Pharmaco-behavioral profiling identifies suppressors of autism gene–associated phenotypes in zebrafish
Priyanka Jamadagni, Yi Dai, Yunqing Liu, +24 , and Ellen J. Hoffman
Proceedings of the National Academy of Sciences Published:March 16, 2026
DOI:https://doi.org/10.1073/pnas.2518846123
Significance
Advancing from gene discovery to pharmacological candidates in autism spectrum disorder (ASD) remains a central challenge. Here, we leverage the strengths of zebrafish as a scalable in vivo system to screen 520 US FDA-approved drugs and establish a database of their effects on sensory processing and arousal behaviors. Using this database, we nominate pharmacological candidates relevant to specific ASD genes or gene subgroups. By testing these drugs in two ASD gene mutants, we identify novel suppressors of mutant behavioral phenotypes, revealing estrogens, microtubules, mitochondria, and lipid metabolism, as central pathways relevant to select ASD genes for further evaluation. Together, our drug screening pipeline provides a critical path forward for ASD gene–based drug discovery informed by a precision medicine approach.
Abstract
Pharmaco-behavioral screens in scalable in vivo systems have critical advantages for drug discovery relevant to large-effect autism spectrum disorder (ASD) genes. Here, we establish a database and open-source website of the behavioral signatures of 520 US Food and Drug Administration (FDA)-approved drugs using high-throughput assays of basic sensory processing and arousal behaviors in larval zebrafish. By leveraging the behavioral profiles of 9 large-effect ASD gene mutants, we identify enrichment of pharmacological mechanisms that anticorrelate with subgroups of ASD genes with shared behavioral phenotypes. Screening of anticorrelating drugs in mutants of two ASD genes, SCN2A and DYRK1A, uncovers compounds that suppress mutant behavioral phenotypes. We identify estropipate, an estrogen receptor agonist, and paclitaxel, a microtubule inhibitor, as the top suppressors in scn1lab and dyrk1a mutants, respectively, and levocarnitine (LEVO), a mitochondrial modulator and carnitine supplement, as a top suppressor of both mutant behavioral phenotypes. Finally, we find that LEVO rescues regional brain activity deficits and dysregulated lipid metabolic pathways in mutants, as well as signaling deficits in human pluripotent stem cell–derived glutamatergic neurons carrying mutations in SCN2A and DYRK1A, demonstrating conservation of drug rescue across systems. Therefore, our study establishes a pharmaco-behavioral resource for precision medicine-based drug discovery, illuminating targets relevant to large-effect ASD genes.
