In the groundbreaking work by Karmon et al. (
1
) in the current issue of Biological Psychiatry, the authors developed a novel mouse model of activity-dependent neuroprotective
protein (ADNP) syndrome. ADNP syndrome, also known as Helsmoortel–Van Der Aa syndrome,
is a rare complex condition diagnosed in children exhibiting delayed development,
autism spectrum disorder (ASD) traits, and intellectual disability. ADNP mutations are not limited to ASD; thus, the Gozes group discovered ADNP somatic mutations paralleling Alzheimer’s disease (AD) tauopathy (
2
), with ADNP playing pivotal roles in maintaining the DNA/chromatin structure (
3
) and function as well as regulating microtubule vitality (
4
). Indeed, the Gozes group has previously developed an Adnp haploinsufficient mouse model (Adnp+/−), characterized by sexually dependent slower axonal transport, aberrant dendritic
spine formation (
5
), and tau deposition pathology in elderly mice, mimicking ASD and AD. The same group
also discovered and is developing the proline-rich 8-amino-acid peptide NAP (davunetide
or CP201), the smallest neuroprotective motif of ADNP. NAP protects microtubule-dependent
axonal transport and alleviates behavioral deficits in mice (
6
). In their current study, Karmon et al. (
1
) used genome editing to generate transgenic mice carrying the most common human p.Tyr719
ADNP mutation (Tyr). This mouse model exhibits a severe phenotype combining gain of toxic
function as well as loss of function, providing further important information in comparison
to the Adnp+/− model (loss of function) and a platform for drug discovery/development with NAP as
a prototype.
SEE CORRESPONDING ARTICLE ON PAGE 81
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References
- Novel ADNP syndrome mice reveal dramatic sex-specific peripheral gene expression with brain synaptic and tau pathologies.Biol Psychiatry. 2022; 92: 81-95
- Discovery of autism/intellectual disability somatic mutations in Alzheimer’s brains: Mutated ADNP cytoskeletal impairments and repair as a case study.Mol Psychiatry. 2021; 26: 1619-1633
- Proximity labeling identifies a repertoire of site-specific R-loop modulators.Nat Commun. 2022; 13: 53
- Introducing ADNP and SIRT1 as new partners regulating microtubules and histone methylation.Mol Psychiatry. 2021; 26: 6550-6561
- Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome.J Clin Invest. 2018; 128: 4956-4969
- The ADNP syndrome and CP201 (NAP) potential and hope.Front Neurol. 2020; 11608444
- Tauopathy in the young autistic brain: Novel biomarker and therapeutic target.Transl Psychiatry. 2020; 10: 228
- Sex differences in biological processes and nitrergic signaling in mouse brain.Biomedicines. 2020; 8: 124
- The role of nitric oxide in brain disorders: Autism spectrum disorder and other psychiatric, neurological, and neurodegenerative disorders.Redox Biol. 2020; 34101567
- Proteomics of autism and Alzheimer's mouse models reveal common alterations in mTOR signaling pathway.Transl Psychiatry. 2021; 11: 480
Article Info
Publication History
Accepted:
March 21,
2022
Received:
March 20,
2022
Identification
Copyright
© 2022 Society of Biological Psychiatry.
