Novel ADNP Syndrome Mice Reveal Dramatic Sex-Specific Peripheral Gene Expression With Brain Synaptic and Tau Pathologies.

Scientists created mice with a genetic change that causes ADNP syndrome, a rare condition involving autism and intellectual disability. They found that male and female mice were affected differently - females had more immune system changes while males showed more repetitive behaviors and brain protein problems. A treatment called NAP helped correct many of these issues, offering hope for future therapies.

This preclinical study developed mouse models of ADNP syndrome, a rare autism/intellectual disability condition, using CRISPR gene editing. The research revealed dramatic sex-specific differences in gene expression and clinical features. Female mice showed more pronounced changes in immune and cellular aging pathways, while males exhibited greater grooming behaviors and early tau protein accumulation in the brain. Treatment with NAP (a protective protein fragment) corrected many of these abnormalities.

The study identified FOXO3 as a key regulatory gene affected in both mouse models and human patient cells, suggesting potential biomarkers for monitoring treatment response.

Results suggest NAP treatment may benefit ADNP syndrome patients, particularly for brain connectivity and tau pathology. Sex-specific treatment approaches may be warranted. FOXO3 could serve as an accessible biomarker for monitoring treatment response in clinical applications.

This is a preclinical animal study with unclear sample sizes. Findings require validation in human clinical trials. The relationship between mouse behaviors and human ADNP syndrome symptoms needs further confirmation.

ADNP is essential for embryonic development. As such, de novo ADNP mutations lead to an intractable autism/intellectual disability syndrome requiring investigation. Mimicking humans, CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 editing produced mice carrying heterozygous Adnp p.Tyr718∗ (Tyr), a paralog of the most common ADNP syndrome mutation. Phenotypic rescue was validated by treatment with the microtubule/autophagy-protective ADNP fragment NAPVSIPQ (NAP).

RNA sequencing of spleens, representing a peripheral biomarker source, revealed Tyr-specific sex differences (e.g., cell cycle), accentuated in females (with significant effects on antigen processing and cellular senescence) and corrected by NAP. Differentially expressed, NAP-correctable transcripts, including the autophagy and microbiome resilience-linked FOXO3, were also deregulated in human patient-derived ADNP-mutated lymphoblastoid cells. There were also Tyr sex-specific microbiota signatures. Phenotypically, Tyr mice, similar to patients with ADNP syndrome, exhibited delayed development coupled with sex-dependent gait defects.

Speech acquisition delays paralleled sex-specific mouse syntax abnormalities. Anatomically, dendritic spine densities/morphologies were decreased with NAP amelioration. These findings were replicated in the Adnpmouse, including Foxo3 deregulation, required for dendritic spine formation. Grooming duration and nociception threshold (autistic traits) were significantly affected only in males.

Early-onset tauopathy was accentuated in males (hippocampus and visual cortex), mimicking humans, and was paralleled by impaired visual evoked potentials and correction by acute NAP treatment. Tyr mice model ADNP syndrome pathology. The newly discovered ADNP/NAP target FOXO3 controls the autophagy initiator LC3 (microtubule-associated protein 1 light chain 3), with known ADNP binding to LC3 augmented by NAP, protecting against tauopathy. NAP amelioration attests to specificity, with potential for drug development targeting accessible biomarkers.