modeling-ascending-vaginal-infection-preterm-birth-neonatal-morbidity

Modeling Ascending Vaginal Infection, Preterm Birth, and Neonatal Morbidity in Mice

Preterm birth continues to be a primary cause of neonatal mortality and morbidity globally, with limited preventative therapies. There is an imperative ...

University College London

Dystrophin is a protein crucial for maintaining the structural integrity of skeletal muscle. So far, attention has been focused on the role of dystrophin in muscle, in view of the devastating progression of weakness and early death that characterizes Duchenne muscular dystrophy. However, in the last few years, the role of shorter dystrophin isoforms, including development and adult expression-specific mechanisms, has been a greater focus. Within the cerebral landscape, various cell types, such as glia, oligodendrocytes and Purkinje, cerebellar granule and vascular-associated cells express a spectrum of dystrophin isoforms, including Dp427, Dp140, Dp71 and Dp40. The interaction of these isoforms with a multitude of proteins suggests their involvement in neurotransmission, influencing several circuit functions. This review presents the intricate interactions among dystrophin isoforms and diverse protein complexes across different cell types and brain regions, as well as the associated clinical complications. We focus on studies investigating protein interactions with dystrophin in the past 30 years at a biochemical level. In essence, the brain's dystrophin landscape is a thrilling exploration of diversity, challenging preconceptions and opening new avenues for understanding CNS physiology. It also holds potential therapeutic implications for neurological complications involving brain dystrophin deficiency. By revealing the molecular complexities related to dystrophin, this review paves the way for future investigations and therapeutic interventions for this CNS aspect of Duchenne muscular dystrophy.

The role of dystrophin isoforms and interactors in the brain.

Preterm birth (PTB; delivery before 37 weeks), the main cause of neonatal death worldwide, can lead to adverse neurodevelopmental outcomes, as well as lung and gut pathology. PTB can be associated with ascending vaginal infection. Ascending Escherichia coli infection in pregnant mice induces PTB and reduces pup survival. The current study demonstrated that this model recapitulates the pathology observed in human preterm neonates (namely, neuroinflammation, lung injury, and gut inflammation). In neonatal brains, there is widespread cell death, microglial activation, astrogliosis, and reduced neuronal density. The utility of this model was validated by assessing the efficacy of maternal cervical gene therapy with an adeno-associated viral vector containing human β defensin 3. This improved pup survival and reduced tumor necrosis factor alpha mRNA expression in perinatal pup brains exposed to E. coli. This model provides a unique opportunity to evaluate the therapeutic benefit of preterm labor interventions on perinatal pathology.

Ascending Vaginal Infection in Mice Induces Preterm Birth and Neonatal Morbidity.

Duchenne muscular dystrophy (DMD), the most common childhood muscular dystrophy, arises from DMD gene mutations, affecting the production of muscle dystrophin protein. Brain dystrophin-gene products are also transcribed via internal promoters. Their deficiency contributes to comorbidities, including intellectual disability ( ~ 22% of patients), autism ( ~ 6%) and attention deficit disorders ( ~ 18%), representing a major unmet need for patients and families. Thus, improvement of their diagnosis and treatment is needed. Dystrophic mouse models exhibit similar phenotypes, where genetic therapies restoring brain dystrophins improve their behaviour. This suggests that future genetic therapies could address both muscle and brain dysfunction in DMD patients.

Article	Year
The role of dystrophin isoforms and interactors in the brain. Brain : a journal of neurology\| PubMed ID: 39673425	2025
Ascending Vaginal Infection in Mice Induces Preterm Birth and Neonatal Morbidity. The American journal of pathology\| PubMed ID: 39892780	2025
Duchenne muscular dystrophy: recent insights in brain related comorbidities. Nature communications\| PubMed ID: 39900900	2025

Konstantina Tetorou

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