ADNP Gene

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ADNP Gene

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ADNP Gene

Overview

ADNP (Activity-Dependent Neuroprotective Protein) is a homeobox-containing transcription factor essential for brain development and neuronal survival. ADNP is one of the most frequently mutated genes in [autism spectrum disorder](/diseases/autism) (Helsmoortel-Van der Aa syndrome) and has emerged as a critical player in [Alzheimer's disease](/diseases/alzheimers-disease) through its direct interaction with [tau](/proteins/tau). The ADNP-derived peptide NAP (davunetide) represents a promising neuroprotective therapeutic strategy that stabilizes [microtubules](/mechanisms/microtubule-dynamics) and prevents tau pathology.

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ADNP Gene

Overview

Mermaid diagram (expand to render)

ADNP (Activity-Dependent Neuroprotective Protein) is a homeobox-containing transcription factor essential for brain development and neuronal survival. ADNP is one of the most frequently mutated genes in [autism spectrum disorder](/diseases/autism) (Helsmoortel-Van der Aa syndrome) and has emerged as a critical player in [Alzheimer's disease](/diseases/alzheimers-disease) through its direct interaction with [tau](/proteins/tau). The ADNP-derived peptide NAP (davunetide) represents a promising neuroprotective therapeutic strategy that stabilizes [microtubules](/mechanisms/microtubule-dynamics) and prevents tau pathology.

<div class="infobox infobox-gene"> [@mandel2007]
<div class="infobox-header">ADNP</div> [@helsmoortel2014]
<table> [@oz2014]
<tr><td class="infobox-label">Full Name</td><td>Activity-Dependent Neuroprotective Protein</td></tr> [@ivashkopachima2019]
<tr><td class="infobox-label">Gene Symbol</td><td>ADNP</td></tr> [@gozes2020]
<tr><td class="infobox-label">Chromosomal Location</td><td>20q13.13</td></tr> [@grigg2020]
<tr><td class="infobox-label">NCBI Gene ID</td><td>[23394](https://www.ncbi.nlm.nih.gov/gene/23394)</td></tr> [@hacohenkleiman2018]
<tr><td class="infobox-label">OMIM</td><td>[611386](https://omim.org/entry/611386)</td></tr>
<tr><td class="infobox-label">Ensembl ID</td><td>[ENSG00000101126](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000101126)</td></tr>
<tr><td class="infobox-label">UniProt ID</td><td>[Q9H2P0](https://www.uniprot.org/uniprot/Q9H2P0)</td></tr>
<tr><td class="infobox-label">Protein</td><td>[ADNP Protein](/proteins/adnp-protein)</td></tr>
<tr><td class="infobox-label">Associated Diseases</td><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Autism (Helsmoortel-Van der Aa)](/diseases/autism), [FTD](/diseases/frontotemporal-dementia), [Parkinson's disease](/diseases/parkinsons-disease)</td></tr>
</table>
</div>

Function

ADNP encodes a 1,102 amino acid protein containing a homeobox domain, nine zinc fingers, and a PxVxL motif that mediates interaction with the SWI/SNF chromatin remodeling complex through [HP1](/genes/cbx5). ADNP functions at multiple levels in the nervous system:

Transcriptional Regulation

ADNP acts as a transcription factor that regulates the expression of hundreds of genes critical for neuronal development and maintenance. ADNP binds chromatin through its homeobox domain and recruits the BAF (BRG1/BRM-associated factor) chromatin remodeling complex via its PxVxL motif. Target genes include those involved in:

Axon guidance and neural migration ([SLIT1](genes/SLIT1), [ROBO1](genes/ROBO1))
Synaptic plasticity ([BDNF](/genes/bdnf), [ARC](/genes/arc))
[Autophagy](/entities/autophagy) and proteostasis ([BECN1](/genes/becn1), [LC3](/genes/map1lc3b))
Immune modulation ([TNF](/genes/tnf), [IL6](/genes/il6))

Microtubule Stabilization

The ADNP-derived octapeptide NAP (NAPVSIPQ) binds the microtubule end-binding proteins EB1 and EB3, promoting microtubule dynamics and stability. This interaction is critical for:

Maintaining axonal transport integrity via [kinesin](/genes/kif5a) and [dynein](/genes/dync1h1) motor proteins
Stabilizing [dendritic spines](/cell-types/dendritic-spines) through microtubule invasion into spines
Protecting against [tau](/genes/mapt) hyperphosphorylation-induced microtubule destabilization

Tau Interaction

ADNP directly interacts with [tau protein](/proteins/tau) through the SH3-binding domain. Notably:

ADNP competes with [FYN](/genes/fyn) kinase for tau binding at the dendritic compartment
ADNP-tau interaction protects against tau-mediated toxicity at the [postsynaptic density](/cell-types/postsynaptic-densities)
Loss of ADNP function leads to tau hyperphosphorylation and tauopathy

Disease Associations

Helsmoortel-Van der Aa Syndrome (ADNP Syndrome)

De novo mutations in ADNP are one of the most common single-gene causes of autism, accounting for approximately 0.17% of ASD cases. Over 50 pathogenic mutations have been identified, predominantly truncating variants in exon 5. Clinical features include:

Intellectual disability and global developmental delay
Autism spectrum features (social communication deficits, repetitive behaviors)
Hypotonia and motor planning difficulties
Characteristic facial features
Feeding difficulties in early life

Alzheimer's Disease

ADNP has a multifaceted relationship with [Alzheimer's disease](/diseases/alzheimers-disease):

ADNP expression increases early in AD as a compensatory neuroprotective response but declines in advanced stages
ADNP protein levels in serum and lymphocytes are reduced in mild cognitive impairment (MCI) and AD patients compared to controls
ADNP haploinsufficiency in mouse models produces tauopathy, neuroinflammation, and cognitive deficits
ADNP p.Tyr719* mutation carriers develop early-onset dementia with tau and [TDP-43](/mechanisms/tdp-43-proteinopathy) pathology
The NAP peptide derived from ADNP protects against [amyloid-beta](/proteins/amyloid-beta) toxicity in neuronal cultures

Tauopathies and Frontotemporal Dementia

ADNP mutations produce a specific pattern of tau pathology:

Hyperphosphorylated tau deposits in frontal and temporal cortices
Comorbid [TDP-43](/genes/tardbp) pathology, suggesting shared proteostatic mechanisms
ADNP deficiency promotes tau missorting from axons to the somatodendritic compartment

Parkinson's Disease

Reduced ADNP expression has been reported in the [substantia nigra](/brain-regions/substantia-nigra) of PD patients. The NAP peptide protects dopaminergic [neurons](/entities/neurons) against [MPTP](/mechanisms/mptp-model)-induced toxicity in animal models.

Expression

ADNP is broadly expressed throughout the brain with highest levels in:

Cerebral [cortex](/brain-regions/cortex) — particularly prefrontal and temporal regions
[Hippocampus](/brain-regions/hippocampus) — [CA1](/cell-types/ca1-pyramidal-neurons) and [CA3](/cell-types/ca3-pyramidal-neurons) pyramidal neurons, [dentate gyrus](/cell-types/dentate-gyrus-granule-cells)
Cerebellum — Purkinje cells and granule cells
Hypothalamus and thalamus
[Astrocytes](/entities/astrocytes) — ADNP is expressed in both neurons and [astrocytes](/cell-types/astrocytes), with astrocytic ADNP contributing to neuroprotective paracrine signaling

Expression pattern via [Allen Brain Atlas](https://portal.brain-map.org/).

Therapeutic Targeting

NAP/Davunetide (AL-108)

The NAP peptide (NAPVSIPQ), derived from the ADNP active site, is the most advanced ADNP-based therapeutic:

Mechanism: Stabilizes microtubules via EB1/EB3 binding, protects against tau pathology, reduces neuroinflammation
Clinical trials: Phase II trials in amnestic MCI showed improved memory; Phase II/III trial in [progressive supranuclear palsy](/diseases/progressive-supranuclear-palsy) (PSP) did not meet primary endpoints but showed biomarker improvements
Intranasal delivery: AL-108 formulation demonstrated CNS penetration and cognitive benefits in preclinical models
Combination potential: NAP synergizes with the ADNP-derived peptide SKIP, enhancing neuroprotection

CP201 (ADNP Gene Therapy)

Gene therapy approaches using AAV-ADNP are being developed for ADNP syndrome, showing restoration of social behavior and cognitive function in Adnp-haploinsufficient mice.

Key Publications

External Links

[NCBI Gene: ADNP](https://www.ncbi.nlm.nih.gov/gene/23394)
[UniProt: Q9H2P0](https://www.uniprot.org/uniprot/Q9H2P0)
[OMIM: 611386](https://omim.org/entry/611386)
[GeneCards: ADNP](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADNP)

References

[Bassan et al., Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide (1999) (1999)](https://doi.org/10.1046/j.1471-4159.1999.0721283.x)

[Mandel et al., Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate genes essential for embryogenesis (2007) (2007)](https://doi.org/10.1002/dvdy.21265)

[Helsmoortel et al., A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP (2014) (2014)](https://doi.org/10.1038/ng.2899)

[Oz et al., The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins (2014) (2014)](https://doi.org/10.1038/mp.2013.152)

[Ivashko-Pachima et al., Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments are reversed by NAP (2019) (2019)](https://doi.org/10.1038/s41380-019-0428-1)

[Unknown, Gozes I., The ADNP Syndrome and CP201 (NAP) Potential and Hope (2020) (2020)](https://doi.org/10.3389/fnins.2020.00225)

[Grigg et al., Tauopathy in the young autistic brain: novel biomarker and therapeutic target (2020) (2020)](https://doi.org/10.1038/s41398-020-0751-4)

[Hacohen-Kleiman et al., ADNP/NAP dramatically increase microtubule end-binding protein-tau interaction: a novel avenue for protection against tauopathy (2018) (2018)](https://doi.org/10.1038/s41380-017-0004-6)

Pathway Diagram

The following diagram shows the key molecular relationships involving ADNP Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

ADNP

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wiki_page_id	wp-b8dfc74cbcb0
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📊 Evidence Profile Foundational

Evidence Balance

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Outgoing

31

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📗 Cite This Artifact

ADNP Gene

ADNP Gene

Overview

ADNP Gene

Overview

Function

Transcriptional Regulation

Microtubule Stabilization

Tau Interaction

Disease Associations

Helsmoortel-Van der Aa Syndrome (ADNP Syndrome)

Alzheimer's Disease

Tauopathies and Frontotemporal Dementia

Parkinson's Disease

Expression

Therapeutic Targeting

NAP/Davunetide (AL-108)

CP201 (ADNP Gene Therapy)

Key Publications

External Links

References

Pathway Diagram

💬 Discussion