ArticleMolecular psychiatry2022
SH3- and actin-binding domains connect ADNP and SHANK3, revealing a fundamental shared mechanism underlying autism.
Article in Molecular psychiatry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 64 citations in OpenAlex.
- Systemic davunetide provides sex-specific neuroprotection during Coronary Artery Bypass Grafting (CABG).Translational psychiatry · 2025Trial
- Davunetide sex-dependently boosts memory in prodromal Alzheimer's disease.Translational psychiatry · 2024Trial
- Myelin, white matter, and social deficits in autism spectrum disorder.Neural regeneration research · 2026Article
- ADNP Functions During Early Brain Development and Their Relevance to ASD and ADNP Syndrome.International journal of molecular sciences · 2026Review
- Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women.Molecular psychiatry · 2026Article
- An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice.EBioMedicine · 2026Article
- Transient visual evoked potential abnormalities in ADNP syndrome.Journal of neurodevelopmental disorders · 2026Article
- Digestive Neurobiology in Autism: From Enteric and Central Nervous System Interactions to Shared Genetic Pathways.International journal of molecular sciences · 2025Review
- ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation.Molecular psychiatry · 2025Article
- The multifaceted role of mitochondria in autism spectrum disorder.Molecular psychiatry · 2025Review
- DeepDrug as an expert guided and AI driven drug repurposing methodology for selecting the lead combination of drugs for Alzheimer's disease.Scientific reports · 2025Article
- Modulation of axon excitable domains by astrocytes and microglia.Frontiers in cellular neuroscience · 2025Review
- Sex-Specific ADNP/NAP (Davunetide) Regulation of Cocaine-Induced Plasticity.Journal of molecular neuroscience : MN · 2024Article
- Tracing the invisible mutant ADNP protein in Helsmoortel-Van der Aa syndrome patients.Scientific reports · 2024Article
- ADNP dysregulates methylation and mitochondrial gene expression in the cerebellum of a Helsmoortel-Van der Aa syndrome autopsy case.Acta neuropathologica communications · 2024Article
- Disrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium.Molecular psychiatry · 2024Article
- Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males.Journal of molecular neuroscience : MN · 2024Article
- Clinical impact and in vitro characterization of ADNP variants in pediatric patients.Molecular autism · 2024Article
- A guide to selecting high-performing antibodies for ADNP (UniProt ID: Q9H2P0) for use in western blot, immunoprecipitation, and immunofluorescence.F1000Research · 2024Article
- Unexpected gender differences in progressive supranuclear palsy reveal efficacy for davunetide in women.Translational psychiatry · 2023Article
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
De novo heterozygous mutations in activity-dependent neuroprotective protein (ADNP) cause autistic ADNP syndrome. ADNP mutations impair microtubule (MT) function, essential for synaptic activity. The ADNP MT-associating fragment NAPVSIPQ (called NAP) contains an MT end-binding protein interacting domain, SxIP (mimicking the active-peptide, SKIP). We hypothesized that not all ADNP mutations are similarly deleterious and that the NAPV portion of NAPVSIPQ is biologically active. Using the eukaryotic linear motif (ELM) resource, we identified a Src homology 3 (SH3) domain-ligand association site in NAP responsible for controlling signaling pathways regulating the cytoskeleton, namely NAPVSIP. Altogether, we mapped multiple SH3-binding sites in ADNP. Comparisons of the effects of ADNP mutations p.Glu830synfs*83, p.Lys408Valfs*31, p.Ser404* on MT dynamics and Tau interactions (live-cell fluorescence-microscopy) suggested spared toxic function in p.Lys408Valfs*31, with a regained SH3-binding motif due to the frameshift insertion. Site-directed-mutagenesis, abolishing the p.Lys408Valfs*31 SH3-binding motif, produced MT toxicity. NAP normalized MT activities in the face of all ADNP mutations, although, SKIP, missing the SH3-binding motif, showed reduced efficacy in terms of MT-Tau interactions, as compared with NAP. Lastly, SH3 and multiple ankyrin repeat domains protein 3 (SHANK3), a major autism gene product, interact with the cytoskeleton through an actin-binding motif to modify behavior. Similarly, ELM analysis identified an actin-binding site on ADNP, suggesting direct SH3 and indirect SHANK3/ADNP associations. Actin co-immunoprecipitations from mouse brain extracts showed NAP-mediated normalization of Shank3-Adnp-actin interactions. Furthermore, NAP treatment ameliorated aberrant behavior in mice homozygous for the Shank3 ASD-linked InsG3680 mutation, revealing a fundamental shared mechanism between ADNP and SHANK3.
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