Novel ADNP syndrome mice reveal dramatic sex-specific peripheral gene expression with brain synaptic and Tau pathologies

Abstract Background Activity-dependent neuroprotective protein (ADNP) is essential for embryonic development. As such, de novo ADNP mutations lead to an intractable autism/intellectual disability syndrome requiring investigation. Methods Mimicking humans, CRISPR-Cas9 editing produced mice carrying heterozygous Adnp p.Tyr718* (“Tyr”, paralogue of the most common ADNP syndrome mutation). Phenotypic rescue was validated by treatment with the microtubule/autophagy-protective ADNP fragment, NAP (NAPVSIPQ). Results 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 forkhead box O3 (FOXO3) were also deregulated in human patient-derived ADNP mutated lymphoblastoid cells. There were also Tyr-sex-specific microbiota signatures. Phenotypically, Tyr-mice, like ADNP syndrome patients, 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 Adnp+/- mouse, 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 were paralleled by impaired visual evoked potentials and correction by acute NAP treatment. Conclusions /Discussion: Tyr-mice model ADNP syndrome pathology. The newly discovered ADNP/NAP target FOXO3, controls the autophagy-initiator, microtubule-associated-protein1-light-chain3 (LC3), 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.