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The role of transglutaminase family in central nervous system diseases: From molecular mechanisms to therapeutic targets
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DOI：10.1016/j.gendis.2026.102392.png)
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Abstract
En 中文
The transglutaminase (TG) family comprises calcium-dependent enzymes that catalyze covalent ε-(γ-glutamyl)lysine isopeptide bond formation between glutamine and lysine residues, thereby promoting protein cross-linking, polymerization, and stabilization, while also exerting important non-enzymatic functions in the central nervous system (CNS) through conformation-dependent signaling and scaffolding. Among TG family members, transglutaminase 2 (TGM2) is the best-characterized CNS isoenzyme, whereas TGM6 is predominantly neuronal. Under physiological conditions, TGs contribute to neuronal structure, myelination-related processes, synaptic remodeling, and neural circuit homeostasis; however, increasing evidence indicates that TG dysregulation is involved in multiple CNS disorders and extends beyond passive bystander up-regulation. In this review, we propose that TG family members, particularly TGM2, form a TG–pathology axis linking proteostasis disruption and neuroimmune activation. In pathological contexts, TG-driven pathways may promote pathogenic protein aggregation, amplify inflammatory signaling, and facilitate cell death, thereby contributing to the progression from early, potentially reversible cellular stress to persistent and progressive pathology. Importantly, these effects are highly context-dependent, varying with coenzymes, cell type, subcellular localization, and disease stage, and different TG isoenzymes may exert distinct or even opposing roles despite sharing a common cross-linking chemistry. We summarize the structural basis, enzymatic and non-enzymatic functions, and disease-specific roles of TG family members in neurodegenerative, neuroinflammatory, cerebrovascular, and injury-related CNS disorders and further evaluate current genetic and pharmacological evidence, emerging therapeutic strategies, and key barriers to clinical translation to provide an updated framework for the development of more precise TG-targeted interventions in CNS disease.
Keywords:
Central nervous system disorders
Neurodegeneration
Proteostasis
TGM2
Transglutaminase
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