Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome

J Clin Invest. 2018 Nov 1;128(11):4956-4969. doi: 10.1172/JCI98199. Epub 2018 Sep 24.


Previous findings showed that in mice, complete knockout of activity-dependent neuroprotective protein (ADNP) abolishes brain formation, while haploinsufficiency (Adnp+/-) causes cognitive impairments. We hypothesized that mutations in ADNP lead to a developmental/autistic syndrome in children. Indeed, recent phenotypic characterization of children harboring ADNP mutations (ADNP syndrome children) revealed global developmental delays and intellectual disabilities, including speech and motor dysfunctions. Mechanistically, ADNP includes a SIP motif embedded in the ADNP-derived snippet drug candidate NAP (NAPVSIPQ, also known as CP201), which binds to microtubule end-binding protein 3, essential for dendritic spine formation. Here, we established a unique neuronal membrane-tagged, GFP-expressing Adnp+/- mouse line allowing in vivo synaptic pathology quantification. We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment. Adnp+/-mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal). In conclusion, we have connected ADNP-related synaptic pathology to developmental and behavioral outcomes, establishing NAP in vivo target engagement and identifying potential biomarkers. Together, these studies pave a path toward the clinical development of NAP (CP201) for the treatment of ADNP syndrome.

Keywords: Drug therapy; Therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Video-Audio Media

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Autistic Disorder / genetics
  • Autistic Disorder / metabolism*
  • Autistic Disorder / pathology
  • Autistic Disorder / physiopathology
  • Behavior, Animal
  • Biomarkers / metabolism
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Cell Membrane / pathology
  • Dendritic Spines / metabolism*
  • Dendritic Spines / pathology
  • Gene Expression Regulation
  • Homeodomain Proteins
  • Humans
  • Mice
  • Mice, Knockout
  • Microtubules / genetics
  • Microtubules / metabolism
  • Microtubules / pathology
  • Models, Neurological*
  • Mutation
  • Naphthoquinones / pharmacology
  • Nerve Tissue Proteins / deficiency*
  • Synapses / metabolism*
  • Synapses / pathology
  • Syndrome


  • 2-(3,5-di-tert-butyl-4-hydroxyl)-3-chloro-1,4-naphthoquinone
  • Adnp protein, mouse
  • Biomarkers
  • Homeodomain Proteins
  • Naphthoquinones
  • Nerve Tissue Proteins

Grants and funding

G.H.K. and S.S. are supported by Eshkol fellowships, the Israel Ministry of Science and Technology. S.S. is further supported by the Tel Aviv University Global Research & Training Fellowship and The Naomi Foundation, as well as The Eldee Foundation/Bloomfield Family of Montreal awards for student exchange (Tel Aviv University/McGill University). V.K. is supported by the CAS (RVO: 86652036) and LQ1604 NPU II, project BIOCEV (CZ.1.05/1.1.00/02.0109) from the ERDF, and MEYS CR. I. Gozes is supported by the following grants, ISF 1424/14, ERA-NET neuron AUTYSM, AMN Foundation as well as Drs. Ronith and Armand Stemmer, Mr Arthur Gerbi (French Friends of Tel Aviv University), and Spanish Friends of Tel Aviv University. R.A. McKinney is supported by CIHR.