Biology subjects

Demireva, E.

Publications and source records attributed to Demireva, E..

2 recordsLinked to original sources

bioRxiv2025

Autoimmune regulator deficiency causes sterile epididymitis and impacts male fertility through disruption of inorganic physiology

Autoimmune regulator (AIRE), a transcription factor expressed by medullary thymic epithelial cells, is required for shaping the self-antigen tolerant T cell receptor repertoire. Humans with mutations in AIRE suffer from Autoimmune Polyglandular Syndrome Type 1 (APS-1). Among many symptoms, men with APS-1 commonly experience testicular insufficiency and infertility, but the mechanisms causing infertility are unknown. Using an Aire-deficient mouse model, we demonstrate that male subfertility is caused by sterile epididymitis characterized by immune cell infiltration and extensive fibrosis. In addition, we reveal that the presence of autoreactive immune cells and inflammation in epididymides of Aire-deficient mice are required for iron (Fe) deposition in the interstitium, which is brought on by macrophages. We further demonstrate that male subfertility is associated with a decrease in metals zinc (Zn), copper (Cu), and selenium (Se) which serve as cofactors in several antioxidant enzymes. We also show increase in DNA damage of epididymal sperm of Aire-/- animals as a key contributing factor to subfertility. The absence of Aire results in autoimmune attack of the epididymis leading to fibrosis, Fe deposition, and Cu, Zn and Se imbalance, ultimately resulting in sperm DNA damage and subfertility. These results highlight the requirement of Aire to promote immune tolerance throughout the epididymis, disruption of which causes an imbalance of inorganic elements with resulting consequence on male fertility. Key pointsBreakdown of epididymal self-tolerance promotes disruption of inorganic elements. Autoimmunity causes interstitial fibrosis resulting in sperm DNA damage and subfertility. Elevated interstitial iron and macrophages contribute to fibrosis.

pathology↗

bioRxiv2018

Mouse Models of GNAO1-Associated Movement Disorder: Allele- and sex-specific differences in phenotypes

Background\n\nInfants and children with dominant de novo mutations in GNAO1 exhibit movement disorders, epilepsy, or both. Children with loss-of-function (LOF) mutations exhibit Epileptiform Encephalopathy 17 (EIEE17). Gain-of-function (GOF) mutations or those with normal function are found in patients with Neurodevelopmental Disorder with Involuntary Movements (NEDIM). There is no animal model with a human mutant GNAO1 allele.\n\nObjectives\n\nHere we develop a mouse model carrying a human GNAO1 mutation and determine whether clinical features of the GNAO1 mutation including movement disorder would be evident in the mouse model.\n\nMethods\n\nA mouse Gnao1 knock-in GOF mutation (G203R) was created by CRISPR/Cas9 methods. The resulting offspring and littermate controls were subjected to a battery of behavioral tests. A previously reported GOF mutant mouse knock-in (Gnao1+/G184S) was also studied for comparison.\n\nResults\n\nGnao1+/G203R mutant mice are viable and gain weight comparably to controls. Homozygotes are non-viable. Grip strength was decreased in both males and females. Male Gnao1+/G203R mice were strongly affected in movement assays (RotaRod and DigiGait) while females were not. Male Gnao1+/G203R mice also showed enhanced seizure propensity in the pentylenetetrazole kindling test. Mice with a G184S GOF knock-in also showed movement-related behavioral phenotypes but females were more strongly affected than males.\n\nConclusions\n\nGnao1+/G203R mice phenocopy children with heterozygous GNAO1 G203R mutations, showing both movement disorder and a relatively mild epilepsy pattern. This mouse model should be useful in mechanistic and preclinical studies of GNAO1-related movement disorders.

animal behavior and cognition↗