Fruit Fly and Human Brain Enzymes Prove Partly Interchangeable Across 600 Million Years of Evolution

In a finding that underscores how deeply conserved the molecular logic of brain building really is, researchers in Chile and the United States have shown that a human brain enzyme can step in for its fruit fly counterpart and rescue key features of a developing nervous system. The study, published in Cellular and Molecular Life Sciences, focuses on transglutaminases, a family of calcium-dependent enzymes that chemically modify proteins, and demonstrates that the single transglutaminase gene of Drosophila melanogaster and at least one human family member, transglutaminase 6, are partially interchangeable. The work, led by Isidora Almonacid-Torres and Jorge M. Campusano at the Pontificia Universidad Católica de Chile, together with colleagues including Ian Maze at the Icahn School of Medicine at Mount Sinai, offers a striking example of evolutionary conservation at the level of brain development and behavior.

Transglutaminases catalyze transamidation reactions, a calcium-dependent chemistry that forms new bonds between proteins and can attach small amines to protein targets. In mammals, the family includes several members, and in higher mammals transglutaminase 2, commonly abbreviated TG2, is the most abundantly expressed form in the brain. Yet when scientists knocked out TG2 in mice, the animals showed no major neurodevelopmental abnormalities. That puzzling result has long suggested that other transglutaminase family members expressed in the mammalian central nervous system may compensate for the loss, masking the true importance of these enzymes during brain formation. Compensation of this kind makes mammalian genetics a blunt instrument for probing what transglutaminases actually do as the brain takes shape.

This is precisely where the fruit fly offers an advantage. Drosophila melanogaster carries only a single transglutaminase gene, known as dTg, which means that removing it eliminates the entire enzymatic family in one genetic stroke. There is no redundancy to hide behind. Despite this experimental appeal, the contribution of dTg to brain development and function had remained poorly understood, and the new study set out to fill that gap by asking what happens to the fly nervous system, and to fly behavior, when dTG is absent.

The answer, at the structural level, was unambiguous. Animals lacking functional dTG displayed defects in the mushroom body, the fly brain structure that serves as a crucial associative learning center and is often compared, in function, to parts of the mammalian cortex and hippocampus. The mutants also showed abnormalities in brain dopaminergic neurons, the cells that produce and release dopamine, both when examined in living animals and when the neurons were grown in vitro. Because dopaminergic systems in flies, as in humans, govern movement, motivation, and social behavior, these anatomical findings pointed toward functional consequences that the team then went on to test directly.

Those consequences were readily apparent in the behavior of the mutant animals. Flies deficient in dTG showed altered locomotion, a hallmark of dopaminergic dysfunction, and, more strikingly, a strong asocial-like phenotype. Social behavior in Drosophila is a well-established experimental readout, and disruptions of dopamine signaling are known to alter how flies aggregate, interact, and respond to one another. The concordance between the structural defects in dopaminergic neurons and the behavioral abnormalities in movement and social interaction strengthened the case that transglutaminase activity is genuinely required for the proper maturation of these neuronal populations and the circuits they build, rather than producing incidental or downstream effects.

To understand the molecular basis of these defects, the researchers turned to transcriptomics, profiling gene expression across the fly brain. In dTG-deficient animals, the expression of numerous genes associated with neurogenesis and neurodevelopment was altered. This pattern suggests that transglutaminase activity influences the transcriptional programs that guide neural progenitors and young neurons as they differentiate and wire into circuits. In other words, the enzyme appears to act upstream of gene regulation during brain maturation, not merely as a structural accessory protein, and its absence ripples outward through the developmental transcriptome.

The most provocative experiment, however, was the one that crossed the species boundary. When the researchers expressed human transglutaminase 6, hTG6, in the fly under the control of the endogenous dTg promoter, meaning the human enzyme was produced exactly where and when the fly enzyme would normally be, the results were remarkable. The human enzyme rescued the social phenotype of the mutants and prevented the loss of dopaminergic neurons. It also partially reverted the changes in gene expression observed in the mutants and partially corrected the motor defects. A human protein, operating in an insect brain, could substantially stand in for the fly’s own enzyme, a demonstration of functional conservation spanning roughly 600 million years of independent evolution.

Why only partial rescue? The authors point to epigenetics, specifically a chemical mark known as histone dopaminylation. This modification, in which dopamine itself is attached to histone proteins around which DNA is wrapped, links neuronal activity and dopamine signaling to the regulation of gene expression, and transglutaminase enzymes have been implicated in catalyzing it. In the dTG mutants, this epigenetic mark is disrupted, and the expression of hTG6 only partially restores it. That incomplete restoration of histone dopaminylation provides a coherent mechanistic explanation for the incomplete rescue of the transcriptomic, motor, and behavioral phenotypes, and it ties the developmental role of transglutaminases to the emerging field of dopamine-driven epigenetic regulation in the brain.

Taken together, the findings carry two significant implications. First, they support the idea that the functions of transglutaminases in the nervous system are evolutionarily conserved across species, from insects to humans, and that these enzymes contribute to the maturation of brain neurons and circuits in a fundamentally similar way. Second, they validate the fly as a streamlined model for studying transglutaminase biology in the brain. Because Drosophila has only one transglutaminase gene, researchers can dissect the enzyme’s roles without the confounding compensation that complicates mammalian studies, and the partial interchangeability with human TG6 means that discoveries made in the fly are likely to be relevant to human neurobiology.

The study also resonates beyond basic developmental neuroscience. Transglutaminases have been linked to human neurological conditions, and the related subjects highlighted alongside the article include Huntington’s disease and amyotrophic lateral sclerosis, disorders in which protein chemistry, neuronal vulnerability, and brain circuit dysfunction intersect. While the current work does not establish a direct therapeutic pathway, it clarifies the normal developmental functions of these enzymes and demonstrates that their activity shapes dopaminergic neurons and social behavior through conserved molecular mechanisms. As research into histone dopaminylation and transglutaminase biology advances, the humble fruit fly, equipped with a single enzyme that a human protein can partially replace, is likely to remain at the center of efforts to understand how brains are built, one calcium-dependent chemical bond at a time.

Subject of Research: Evolutionarily conserved roles of transglutaminase enzymes in Drosophila brain development and dopaminergic neuron maturation

Article Title: Drosophila and human transglutaminases are partially interchangeable, revealing evolutionary conserved roles in brain development

Article References: Almonacid-Torres, I., Almonacid-Torres, J., Gómez-Fett, P., González-Ramírez, M. C., Chamorro-González, A., Zárate, R. V., Maze, I., Oliva, C., Andrés, M. E., & Campusano, J. M. (2026). Drosophila and human transglutaminases are partially interchangeable, revealing evolutionary conserved roles in brain development. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06413-9

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06413-9

Keywords: transglutaminase, Drosophila, human TG6, dopaminergic neurons, brain development, mushroom body, histone dopaminylation, neurogenesis, epigenetics, locomotion, social behavior, evolutionary conservation