Molecular Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 23, 2024

Abstract Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical neurogenesis cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism somatic parallel Alzheimer’s disease progression. Furthermore, clinical trials with the fragment NAP (the investigational drug davunetide) showed efficacy women suffering from tauopathy progressive supranuclear palsy differentially boosted memory men (spatial) (verbal), exhibiting prodromal disease. While more prevalent boys women, both involve impaired neurogenesis. Here, we asked whether sex-dependently regulates Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, identified two-fold higher labeling hippocampal sub-ventricular zone ADNP-intact male versus female mice. Adnp haplo-insufficient ( +/− ) mice or CRSIPR/Cas9-edited present most neurodevelopmental syndrome mutation, p.Tyr718* (Tyr) dramatic reductions BrdU incorporation, resulting mutated females presenting than males. Treatment compensated reduction labeling. Mechanistically, RNAseq revealed male-specific Tyr down-regulation endoplasmic reticulum unfolded response genes sex-dependent organogenesis. Newly discovered mitochondrial accessibility was inhibited by Tyr718* mutation further revealing female-specific downregulation ATP6 . moderated much differential expression caused p.Tyr718*, accompanied neurotoxic, pro-inflammatory pro-apoptotic genes. Thus, key regulator that acts controlling canonical pathways, compensating fundamental deficiencies, striding toward development targeting related neurodevelopmental/neurodegenerative diseases.

Language: Английский