A GluN2B disease-associated variant promotes degradation of NMDA receptors via autophagy

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 13, 2025

Abstract N-methyl-D-aspartate receptors (NMDARs) are essential for excitatory neurotransmission and their pathogenic variants can lead to proteostasis defects thus neurological diseases. However, how the network degrades is not well understood. Here, we demonstrated that R519Q GluN2B variant retained in endoplasmic reticulum (ER) fails traffic surface form functional NMDARs. Pharmacological genetic inhibition of autophagy results accumulation this variant, indicating it degraded by autophagy-lysosomal proteolysis pathway. Since has a cytosolic LIR motif, which interact with machinery, disrupting motif impairs autophagic clearance variant. Additionally, recognized ER-phagy receptors, including CCPG1 RTN3L. Our result provides molecular mechanism degradation NMDAR identifies pathway targeted therapeutic intervention disorders dysfunctional Summary NMDA Benske et al. report predispose subunits

Язык: Английский

Characterization of prostate macrophage heterogeneity, foam cell markers, and CXCL17 upregulation in a mouse model of steroid hormone imbalance

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Сен. 9, 2024

Benign prostatic hyperplasia (BPH) is a prevalent age-related condition often characterized by debilitating urinary symptoms. Its etiology believed to stem from hormonal imbalance, particularly an elevated estradiol-to-testosterone ratio and chronic inflammation. Our previous studies using mouse steroid hormone imbalance model identified specific increase in macrophages that migrated accumulated the prostate lumen where they differentiated into lipid-laden foam cells mice implanted with testosterone estradiol pellets, but not sham animals. The current study focused on further characterizing cellular heterogeneity of this as well identifying transcriptomic signature recruited cells. Moreover, we aimed identify epithelia-derived signals drive macrophage infiltration luminal translocation. Male C57BL/6J were slow-release pellets (T + E2) or surgery was performed ventral prostates harvested two weeks later for scRNA-seq analysis. We Ear2 Cd72 response whereas Mrc1 resident population did change. In addition, Spp1 cell cluster almost exclusively found T E2 mice. Further markers also identified, including Gpnmb Trem2, GPNMB confirmed novel histological marker immunohistochemistry. Foam shown express known pathological factors Vegf, Tgfb1, Ccl6, Cxcl16 Mmp12. Intriguingly, screen chemokines upregulation Cxcl17, monocyte attractant, suggesting it might be responsible number their translocation lumen. subsets responded potential role prostate. These results underscore suggests CXCL17-mediated migration critical initiating event.

Язык: Английский

Context matters: Integrative NMDA receptor dysfunction reveals effective seizure treatment in mice with a human patient GluN1 variant

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Abstract Intractable epilepsy and cognitive deficits arise from missense variants in GRIN genes encoding subunits of the N-Methyl-D-Aspartate receptor (NMDAR). Here, we go beyond typical assessments isolated receptors to explore impact a human GluN1 variant across multiple scales native NMDAR signaling. We show that integrated signaling are differentially affected brain slices transgenic mice with heterozygous Y647S patient variant. Loss-of-function NMDARs paradoxically prolong NMDAR-dependent dendritic integration, extending cortical network activity increasing vulnerability for seizure-like events. identify loss-of-function fail engage canonical negative feedback via calcium-activated potassium channels. To prevent hyperexcitability overdrive, test an unorthodox treatment increase Mg 2+ block. Oral magnesium-L-threonate significantly reduces seizure occurrence severity mice. This work demonstrates higher-order functional context is useful predicting effective seizures arising disruption. One line summary Using patient-variant NMDA receptors, through excessive excitation caused by impaired feedback. Targeting this mechanism treats seizures, underscoring importance treating dysfunction.

Язык: Английский