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Sex and the Brain: Novel ADNP Syndrome Mice Are Protected by NAP

      In the groundbreaking work by Karmon et al. (
      • Karmon G.
      • Sragovich S.
      • Hacohen-Kleiman G.
      • Ben-Horin-Hazak I.
      • Kasparek P.
      • Schuster B.
      • et al.
      Novel ADNP syndrome mice reveal dramatic sex-specific peripheral gene expression with brain synaptic and tau pathologies.
      ) 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 (
      • Ivashko-Pachima Y.
      • Hadar A.
      • Grigg I.
      • Korenková V.
      • Kapitansky O.
      • Karmon G.
      • et al.
      Discovery of autism/intellectual disability somatic mutations in Alzheimer’s brains: Mutated ADNP cytoskeletal impairments and repair as a case study.
      ), with ADNP playing pivotal roles in maintaining the DNA/chromatin structure (
      • Yan Q.
      • Wulfridge P.
      • Doherty J.
      • Fernandez-Luna J.L.
      • Real P.F.
      • Yang H.-Y.
      • Sarma K.
      Proximity labeling identifies a repertoire of site-specific R-loop modulators.
      ) and function as well as regulating microtubule vitality (
      • Hadar A.
      • Kapitansky O.
      • Ganaiem M.
      • Sragovich S.
      • Lobyntseva A.
      • Giladi E.
      • et al.
      Introducing ADNP and SIRT1 as new partners regulating microtubules and histone methylation.
      ). Indeed, the Gozes group has previously developed an Adnp haploinsufficient mouse model (Adnp+/−), characterized by sexually dependent slower axonal transport, aberrant dendritic spine formation (
      • Hacohen-Kleiman G.
      • Sragovich S.
      • Karmon G.
      • Gao A.Y.L.
      • Grigg I.
      • Pasmanik-Chor M.
      • et al.
      Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome.
      ), 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 (
      • Gozes I.
      The ADNP syndrome and CP201 (NAP) potential and hope.
      ). In their current study, Karmon et al. (
      • Karmon G.
      • Sragovich S.
      • Hacohen-Kleiman G.
      • Ben-Horin-Hazak I.
      • Kasparek P.
      • Schuster B.
      • et al.
      Novel ADNP syndrome mice reveal dramatic sex-specific peripheral gene expression with brain synaptic and tau pathologies.
      ) 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

        • Karmon G.
        • Sragovich S.
        • Hacohen-Kleiman G.
        • Ben-Horin-Hazak I.
        • Kasparek P.
        • Schuster B.
        • et al.
        Novel ADNP syndrome mice reveal dramatic sex-specific peripheral gene expression with brain synaptic and tau pathologies.
        Biol Psychiatry. 2022; 92: 81-95
        • Ivashko-Pachima Y.
        • Hadar A.
        • Grigg I.
        • Korenková V.
        • Kapitansky O.
        • Karmon G.
        • et al.
        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
        • Yan Q.
        • Wulfridge P.
        • Doherty J.
        • Fernandez-Luna J.L.
        • Real P.F.
        • Yang H.-Y.
        • Sarma K.
        Proximity labeling identifies a repertoire of site-specific R-loop modulators.
        Nat Commun. 2022; 13: 53
        • Hadar A.
        • Kapitansky O.
        • Ganaiem M.
        • Sragovich S.
        • Lobyntseva A.
        • Giladi E.
        • et al.
        Introducing ADNP and SIRT1 as new partners regulating microtubules and histone methylation.
        Mol Psychiatry. 2021; 26: 6550-6561
        • Hacohen-Kleiman G.
        • Sragovich S.
        • Karmon G.
        • Gao A.Y.L.
        • Grigg I.
        • Pasmanik-Chor M.
        • et al.
        Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome.
        J Clin Invest. 2018; 128: 4956-4969
        • Gozes I.
        The ADNP syndrome and CP201 (NAP) potential and hope.
        Front Neurol. 2020; 11608444
        • Grigg I.
        • Ivashko-Pachima Y.
        • Hait T.A.
        • Korenková V.
        • Touloumi O.
        • Lagoudaki R.
        • et al.
        Tauopathy in the young autistic brain: Novel biomarker and therapeutic target.
        Transl Psychiatry. 2020; 10: 228
        • Khaliulin I.
        • Kartawy M.
        • Amal H.
        Sex differences in biological processes and nitrergic signaling in mouse brain.
        Biomedicines. 2020; 8: 124
        • Tripathi M.K.
        • Kartawy M.
        • Amal H.
        The role of nitric oxide in brain disorders: Autism spectrum disorder and other psychiatric, neurological, and neurodegenerative disorders.
        Redox Biol. 2020; 34101567
        • Mencer S.
        • Kartawy M.
        • Lendenfeld F.
        • Soluh H.
        • Tripathi M.K.
        • Khaliulin K.
        • Amal H.
        Proteomics of autism and Alzheimer's mouse models reveal common alterations in mTOR signaling pathway.
        Transl Psychiatry. 2021; 11: 480

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