Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism

Clinical Epigenetics, Journal Year: 2023, Volume and Issue: 15(1)

Published: March 21, 2023

Abstract Background Individuals affected with autism often suffer additional co-morbidities such as intellectual disability. The genes contributing to cluster on a relatively limited number of cellular pathways, including chromatin remodeling. However, information is available how mutations in single can result pleiotropic clinical features individuals. In this review, we summarize one the most frequently mutated syndromic Activity-Dependent Neuroprotective Protein (ADNP). Results Heterozygous and predicted loss-of-function ADNP individuals inevitably presentation Helsmoortel–Van der Aa syndrome, frequent form autism. ADNP, zinc finger DNA-binding protein has role remodeling: associated pericentromeric HP1, SWI/SNF core complex BRG1, other members remodeling and, murine stem cells, chromodomain helicase CHD4 ChAHP complex. recently been shown possess R-loop processing activity. addition, many functions, for instance, association cytoskeletal proteins have linked ADNP. Conclusions We here present an integrated evaluation all current aspects gene function evaluate abnormalities might relate individual“s” syndrome.

Language: Английский

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A novel davunetide (NAPVSIPQQ to NAPVSIPQE) point mutation in activity‐dependent neuroprotective protein (ADNP) causes a mild developmental syndrome

European Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 58(2), P. 2641 - 2652

Published: Jan. 21, 2023

NAP (NAPVSIPQ, drug candidate name, davunetide) is the neuroprotective fragment of activity-dependent protein (ADNP). Recent studies identified NAPVSIP as a Src homology 3 (SH3) domain-ligand association site, responsible for controlling signalling pathways regulating cytoskeleton. Furthermore, SIP motif in NAP/ADNP was crucial direct microtubule end-binding interaction facilitating dynamics and Tau interaction, at site EB1 EB3. Most de novo ADNP mutations reveal heterozygous STOP or frameshift aberrations, driving autistic/intellectual disability-related syndrome. Here, we report first time on missense mutation, resulting containing NAPVISPQE instead NAPVSIPQQ, child presenting developmental hypotonia, possibly associated with inflammation affecting food intake early life coupled fear peer interactions suggestive novel case In silico modelling showed that mutation Q (polar side chain) to E (negative affected electrostatic characteristics (reducing, while scattering positive patch). Comparison most prevalent pathogenic p.Tyr719*, indicated further reduction patch. Previously, exogenous partially ameliorated deficits p.Tyr719* transfected cells CRISPR/Cas9 genome edited cell mouse models. These findings stress importance sequence future putative therapy

Language: Английский

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NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms

Cells, Journal Year: 2023, Volume and Issue: 12(18), P. 2251 - 2251

Published: Sept. 11, 2023

(1) Background: Recently, we showed aberrant nuclear/cytoplasmic boundaries/activity-dependent neuroprotective protein (ADNP) distribution in ADNP-mutated cells. This malformation was corrected upon neuronal differentiation by the ADNP-derived fragment drug candidate NAP (davunetide). Here, investigated mechanism of nuclear protection. (2) Methods: CRISPR/Cas9 DNA-editing established N1E-115 neuroblastoma cell lines that express two different green fluorescent proteins (GFPs)-labeled mutated ADNP variants (p.Tyr718* and p.Ser403*). Cells were exposed to conjugated Cy5, followed live imaging. further characterized using quantitative morphology/immunocytochemistry/RNA quantifications. (3) Results: rapidly distributed cytoplasm also seen nucleus. Furthermore, reduced microtubule content observed lines. In parallel, disrupting microtubules zinc or nocodazole intoxication mimicked mutation phenotypes resulted nuclear-cytoplasmic boundaries, which treatment. No effects noted on levels. Ketamine, used as a control, ineffective, but both ketamine exhibited direct interactions with ADNP, via silico docking. (4) Conclusions: Through microtubule-linked mechanism, localized cytoplasmic compartments, ameliorating ADNP-related deficiencies. These novel findings explain previously published gene expression results broaden (davunetide) utilization research clinical development.

Language: Английский

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Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males

Journal of Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 74(1)

Published: Jan. 29, 2024

Language: Английский

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Transcriptomic Analysis Uncovers an Unfolded Protein Response in ADNP Syndrome

Molecular and Cellular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 11

Published: Feb. 14, 2025

Chromatin regulators are frequently mutated in autism spectrum disorders, but most cases how they cause disease is unclear. Mutations the activity dependent neuroprotective protein (ADNP) causes ADNP syndrome, which characterized by intellectual deficiency and developmental delays. To identify mechanisms that contribute to we used induced pluripotent stem cells derived from syndrome patients as a model test effects of syndromic mutations on gene expression neurodifferentiation. We found some result truncated proteins, displayed aberrant subcellular localization. Gene analyses revealed widespread transcriptional deregulation all tested mutants. Interestingly, mutants show presence fragments ER stress evidenced activation unfolded response (UPR). The showing greatest UPR pathway associated with severe neurodifferentiation survival defects. Our results reveal potential explore new biomarker for severity perhaps also other ASDs where proteins.

Language: Английский

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Extremely Low‐Frequency and Low‐Intensity Electromagnetic Field Technology (ELF‐EMF) Sculpts Microtubules

European Journal of Neuroscience, Journal Year: 2025, Volume and Issue: 61(4)

Published: Feb. 1, 2025

ABSTRACT Aberrant microtubule dynamics coupled with a reduction in Tau‐microtubule interaction are at the core of neuronal injuries resulting disruption and aggregates abnormally phosphorylated Tau. These pathological Tau define tauopathies such as Alzheimer's disease ( AD ), well sequelae following traumatic brain injury (TBI), stroke spinal cord (SCI). We hypothesized that differential applications extremely low‐frequency low‐intensity electromagnetic field (ELF‐EMF) will change function. To examine our hypothesis, we pre‐applied ELF‐EMF to neuroblastoma cell line later exposed 4 h zinc intoxication, modelling dissociation. (40 Hz 1 G; multiple exposure schedules) enhanced increased face toxicity. Complementing these preconditioning neuroprotective effects, concomitant treatment protocols comparing 3.9 or 40 G exposure, indicated effects on phosphorylation accentuated beta tubulin isotypes, depending frequencies, most pronounced Hz. Our results discovered modulation cytoskeleton essential for health.

Language: Английский

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Intranasal NAP (Davunetide): Neuroprotection and circadian rhythmicity

Advanced Drug Delivery Reviews, Journal Year: 2025, Volume and Issue: 220, P. 115573 - 115573

Published: April 4, 2025

In this review we examine the neuroprotective potential of NAP (davunetide), a small peptide derived from Activity-Dependent Neuroprotective Protein (ADNP), in context neurodevelopmental and neurodegenerative disorders. ADNP, protein essential for brain development function, is associated with tauopathy-related diseases, such as Alzheimer's Disease (AD), circadian rhythm regulation. enhances microtubule stability prevents tauopathy. preclinical studies, shows promise improving cognitive performance correcting behavioral deficits different models. Clinical studies on (davunetide) administered via intranasal delivery have demonstrated its safety, favorable bioavailability, efficacy making it viable therapeutic option. pure tauopathy, progressive supranuclear palsy, significantly slowed disease progression women phase II-III clinical trial. Additionally, complex interactions between pathways, regulation extensive compensation upon ADNP deficiency attest to further development. Thus, an example reductionist approach drug delivery, replacing/enhancing critical large ADNP-related pathways including dysregulated microtubules tauopathy bioavailable investigational drug, davunetide.

Language: Английский

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CRISPRi-based screen of autism spectrum disorder risk genes in microglia uncovers roles of ADNP in microglia endocytosis and synaptic pruning

Molecular Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: April 6, 2025

Abstract Autism Spectrum Disorders (ASD) are a set of neurodevelopmental disorders with complex biology. The identification ASD risk genes from exome-wide association studies and de novo variation analyses has enabled mechanistic investigations into how ASD-risk alter development. Most functional genomics have focused on the role these in neurons neural progenitor cells. However, roles for other cell types largely uncharacterized. There is evidence postmortem tissue that microglia, resident immune cells brain, appear activated ASD. Here, we used CRISPRi-based to systematically assess impact gene knockdown microglia activation phagocytosis. We developed an iPSC-derived microglia-neuron coculture system high-throughput flow cytometry readout synaptic pruning enable parallel screening phagocytosis beads, synaptosomes, pruning. Our screen identified ADNP , high-confidence genes, as modifier microglial found loss altered endocytic trafficking, remodeled proteomes, increased motility coculture.

Language: Английский

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Clinical impact and in vitro characterization of ADNP variants in pediatric patients

Molecular Autism, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 22, 2024

Helsmoortel-Van der Aa syndrome (HVDAS) is a rare genetic disorder caused by variants in the activity-dependent neuroprotector homeobox (ADNP) gene; hence, it also called ADNP syndrome. multitasking protein with function as transcription factor, playing critical role brain development. Furthermore, have been identified one of most common single-gene causes autism spectrum (ASD) and intellectual disability. We assembled cohort 15 Chinese pediatric patients, 13 coding region gene, evaluated their clinical phenotypes. Additionally, we constructed corresponding performed western blotting immunofluorescence analysis to examine expression subcellular localization human HEK293T SH-SY5Y cells. Our study conducted thorough characterization manifestations children variants, revealed broad symptoms including global developmental delay, disability, ASD, facial abnormalities, other features. In vitro studies were carried out check variants. Two cases presented missense while remainder exhibited nonsense or frameshift leading truncated mutants overexpression systems. Both overexpressed wildtype all different found be confined nuclei cells; however, distinctive pattern nuclear bodies formed was either partially entirely disrupted mutant proteins. Moreover, two p.Y719* on signal (NLS) pattern, predominantly manifesting cytoplasm limited relatively small sample size absence longitudinal framework monitor progression patient conditions over time. lacked vivo evidence further indicate causal implications reported first HVDAS patients population provided systematic presentations laboratory examinations. multiple validated them vitro. findings offered valuable insights into diverse associated HVDAS.

Language: Английский

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Moderate Physical Activity Increases the Expression of ADNP in Rat Brain

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4382 - 4382

Published: April 16, 2024

Activity-dependent neuroprotective protein (ADNP) is a essential for embryonic development, proper brain and neuronal plasticity. Its mutation causes the autism-like ADNP syndrome (also called Helsmoortel-Van der Aa syndrome), characterized by neural developmental disorders motor dysfunctions. Similar to syndrome, haploinsufficient mouse shows low synapse density, leading cognitive ability delays. Moderate physical activity (PA) has several benefits, promoting survival, differentiation, neurogenesis, Until now, no study investigated effect of moderate exercise on expression distribution in rat brain. The aim current investigation was effects activation measured microtubule β-Tubulin III. In pursuit this objective, twenty-four rats were selected evenly distributed into two categories: sedentary control exposed treadmill over span 12 weeks. Our results showed that PA increases III dentate gyrus (DG) hippocampal region cerebellum. Moreover, we found co-localization both DG cerebellum, suggesting direct association with adult induced PA.

Language: Английский

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