Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome
| Autor: | Andy Y. L. Gao, Illana Gozes, Iris Grigg, Gidon Karmon, Albert Le, Vlasta Korenková, Shlomo Sragovich, Gal Hacohen-Kleiman, Metsada Pasmanik-Chor, R. Anne McKinney |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Dendritic spine Dendritic Spines Amino Acid Motifs Models Neurological Nerve Tissue Proteins Biology Microtubules Neuroprotection Mice 03 medical and health sciences 0302 clinical medicine In vivo Gene expression medicine Animals Humans Autistic Disorder Homeodomain Proteins Mice Knockout Behavior Animal Cell Membrane Syndrome General Medicine medicine.disease Phenotype Nap 030104 developmental biology Gene Expression Regulation Mutation Synapses Autism Haploinsufficiency Neuroscience Biomarkers 030217 neurology & neurosurgery Naphthoquinones Research Article |
| Zdroj: | Journal of Clinical Investigation. 128:4956-4969 |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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