Discovery of Potential Drug Targeting Key Genes in Alzheimer’s Disease: Insights from Transcriptome Analysis and Molecular Docking

Journal of Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 74(2)

Published: May 27, 2024

Language: Английский

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Protective inherited mutations in activity-dependent neuroprotective protein (ADNP): the good, the bad, and the ugly

Genomic psychiatry :, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 7

Published: Nov. 14, 2024

Activity-dependent neuroprotective protein (ADNP), essential for brain formation/function, reveals multiple cytoplasmic and chromatin interacting sites. Computational modeling, alongside the Vineland Adaptive Behavior Scales, a leading instrument supporting diagnosis of intellectual/developmental disabilities, now revealed protective frame shift/stop mutation in ADNP. Thus, woman with inherited mutation, ADNP_Glu931Glyfs * 12 (VB), showed above average performance. Bioinformatics/ silico modeling indicated that while ADNP contains four 14-3-3 interaction sites (instrumental nuclear/cytoplasmic shuttling), an additional fifth site, implicating stronger associations. Furthermore, endogenous (investigational drug, davunetide) NAPVSIPQ (NAP) site was involved 12-14-3-3 interactions. In this respect, also enhanced ADNP-SH3 associations (another NAPVISP 354-361 aa on ADNP, critical cytoskeletal/cellular signaling). HB, 8-year-old VB's son, inheriting mother's further presented heterozygous pathogenic de novo p.Arg730Thrfs 5. However, comparison to carriers similar p.Arg730 (part autistic/intellectual disability syndrome), HB exhibited overall better 3 standard score 70–80 all measures, compared nominal 20 27-year-old subject 100 ± 15 norm, corroborating protection.

Language: Английский

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ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 23, 2024

Abstract Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical neurogenesis cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism somatic parallel Alzheimer’s disease progression. Furthermore, clinical trials with the fragment NAP (the investigational drug davunetide) showed efficacy women suffering from tauopathy progressive supranuclear palsy differentially boosted memory men (spatial) (verbal), exhibiting prodromal disease. While more prevalent boys women, both involve impaired neurogenesis. Here, we asked whether sex-dependently regulates Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, identified two-fold higher labeling hippocampal sub-ventricular zone ADNP-intact male versus female mice. Adnp haplo-insufficient ( +/− ) mice or CRSIPR/Cas9-edited present most neurodevelopmental syndrome mutation, p.Tyr718* (Tyr) dramatic reductions BrdU incorporation, resulting mutated females presenting than males. Treatment compensated reduction labeling. Mechanistically, RNAseq revealed male-specific Tyr down-regulation endoplasmic reticulum unfolded response genes sex-dependent organogenesis. Newly discovered mitochondrial accessibility was inhibited by Tyr718* mutation further revealing female-specific downregulation ATP6 . moderated much differential expression caused p.Tyr718*, accompanied neurotoxic, pro-inflammatory pro-apoptotic genes. Thus, key regulator that acts controlling canonical pathways, compensating fundamental deficiencies, striding toward development targeting related neurodevelopmental/neurodegenerative diseases.

Language: Английский

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Helsmoortel–van der Aa syndrome in a Chinese pediatric patient due to ADNP nonsense mutation: A case report

Frontiers in Pediatrics, Journal Year: 2023, Volume and Issue: 11

Published: March 30, 2023

Helsmoortel-van der Aa syndrome, also known as ADNP is a condition that causes developmental delay, language impairment, autism spectrum, and variable extraneurologic features. It caused by heterozygous mutations in the gene on chromosome 20q13. Most of genetic syndrome have been reported are de novo nonsense or frameshift stop exon 5 gene, while fewer truncating variants were discovered exons 4 5' end 5.In our study, 4-year-old female Chinese patient was with delayed psychomotor development, ataxia, anxiety, aggressive behavior, congenital heart defect. Trio whole exome sequencing copy number variation performed.A novel pathogenic mutation c.568C > T (p.Gln190Ter) identified proband. His unaffected parents did not variant. According to American College Medical Genetics (ACMG) guidelines, classified "pathogenic".Our report indicated cause abnormal development nervous system, disease strabismus, broadening spectrum associated syndrome.

Language: Английский

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Extended phenotypic characterization of a novel Helsmoortel‐van der Aa syndrome case series

American Journal of Medical Genetics Part A, Journal Year: 2024, Volume and Issue: 194(5)

Published: Jan. 10, 2024

Abstract The neurodevelopmental disorder known as Helsmoortel‐van der Aa syndrome (HVDAS, MIM#616580) or ADNP (Orphanet, ORPHA:404448) is a multiple congenital anomaly (MCA) condition, reported in 2014, associated with deleterious variants the gene (activity‐dependent neuroprotective protein; MIM*611386) several children. First turn of century, protein crucial functions for normal development central nervous system and pleiotropic effects, explaining multisystemic character syndrome. Affected individuals present striking facial dysmorphic features variable defects. Herein, we describe novel case series HVDAS Italian patients, illustrating their clinical findings related genotype–phenotype correlations. Interestingly, cutaneous manifestations are also extensively expanded, giving an important contribution to characterization highlighting relation between skin abnormalities

Language: Английский

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CRISPRi-based screen of Autism Spectrum Disorder risk genes in microglia uncovers roles ofADNPin microglia endocytosis and uptake of synaptic material

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

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

Language: Английский

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Blepharophimosis with intellectual disability and Helsmoortel‐Van Der Aa Syndrome share episignature and phenotype

American Journal of Medical Genetics Part C Seminars in Medical Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: June 17, 2024

Abstract Blepharophimosis with intellectual disability (BIS) is a recently recognized disorder distinct from Nicolaides‐Baraister syndrome that presents facial features of blepharophimosis, developmental delay, and disability. BIS caused by pathogenic variants in SMARCA2 , encodes the catalytic subunit superfamily II helicase group BRG1 BRM‐associated factors (BAF) forming BAF complex, chromatin remodeling complex involved transcriptional regulation. Individuals bearing within bipartite nuclear localization (BNL) signal domain ADNP present neurodevelopmental known as Helsmoortel‐Van Der Aa Syndrome (HVDAS). Distinct DNA methylation profiles referred to episignatures have been reported HVDAS disorders. Due molecular interactions between an overlapping craniofacial phenotype narrowing palpebral fissures subset patients BIS, we hypothesized possibility common phenotype‐specific episignature. A episignature was shared 15 individuals BIS‐causing 12 class truncating variants. This represents first evidence sensitive biomarker across genetic conditions also exhibit unique gene‐specific episignatures.

Language: Английский

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Tracing the invisible mutant ADNP protein in Helsmoortel-Van der Aa syndrome patients

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: June 26, 2024

Abstract Heterozygous de novo mutations in the Activity-Dependent Neuroprotective Homeobox ( ADNP ) gene underlie Helsmoortel-Van der Aa syndrome (HVDAS). Most of these are situated last exon and we previously demonstrated escape from nonsense-mediated decay by detecting mutant mRNA patient blood. In this study, wild-type mutants investigated at protein level therefore optimal detection is required. Detection means western blotting has been ambiguous with reported antibodies resulting non-specific bands without unique signal. Validation an N-terminal antibody (Aviva Systems) using a blocking peptide competition assay allowed to differentiate between specific signals different sample materials, band signal around 150 kDa for ADNP, above its theoretical molecular weight 124 kDa. C-terminal confirmed observed Our panel was subsequently tested immunoblotting, comparing parental homozygous CRISPR/Cas9 endonuclease-mediated Adnp knockout cell lines showed disappearance signal, indicative intact ADNP. By both GFPSpark Flag-tag N-terminally fused human expression vector, detected together forms after introduction E. coli systems site-directed mutagenesis. Furthermore, were also able visualize endogenous our heterozygous carrying mutations, while truncated could only be epitope-tag-specific antibodies, suggesting that addition epitope-tag possibly helps stabilizing protein. However, patient-derived hiPSCs, immortalized lymphoblastoid post-mortem brain material failed detect native addition, immunoprecipitation-competent enriched truncating overexpression lysates, whereas implementation same method enrich possible lines. This study aims shape awareness critical assessment analysis syndrome.

Language: Английский

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Proteomics and phosphoproteomics profiling in glutamatergic neurons and microglia in an iPSC model of Jansen de Vries Syndrome

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 8, 2023

Jansen de Vries Syndrome (JdVS) is a rare neurodevelopmental disorder (NDD) caused by gain-of-function (GOF) truncating mutations in PPM1D exons 5 or 6. serine/threonine phosphatase that plays an important role the DNA damage response (DDR) negatively regulating TP53 (P53). JdVS-associated lead to formation of truncated protein retains catalytic activity and has GOF effect because reduced degradation. Somatic 6 are well-established factors number cancers, due excessive dephosphorylation function P53 other substrates involved DDR. Children with JdVS have variety neurodevelopmental, psychiatric, physical problems. In addition, small fraction acute neuropsychiatric decompensation apparently triggered infection severe non-infectious environmental stress factors.To understand molecular basis JdVS, we developed induced pluripotent stem cell (iPSC) model system. iPSCs heterozygous for variant (PPM1D+/tr), were made from patient, control lines engineered using CRISPR-Cas9 gene editing. Proteomics phosphoprotemics analyses carried out on iPSC-derived glutamatergic neurons microglia three PPM1D+/tr iPSC lines. We also analyzed TLR4 agonist, lipopolysaccharide, how activation innate immune system could account behavioral decompensation.One major findings was downregulation POGZ unstimulated microglia. Since loss-of-function variants well-known causes autism spectrum disorder, decrease suggests this aspects JdVS. neurons, baseline, LPS-stimulated show marked alterations expression several E3 ubiquitin ligases, most notably UBR4, regulators immunity, chromatin structure, ErbB signaling, splicing. pathway analysis points overlap neurodegenerative disorders.Owing cost labor-intensive nature research, sample size small.Our provide insight into can be extrapolated occurs subgroups patients ASD NDDs.

Language: Английский

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