BACKGROUND: ADNP is essential for embryonic development. As such, de novo ADNP mutations lead to an intractable autism/intellectual disability syndrome requiring investigation. METHODS: Mimicking humans, CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 editing produced mice carrying heterozygous Adnp p.Tyr718∗ (Tyr), a paralog of the most common ADNP syndrome mutation. Phenotypic rescue was validated by treatment with the microtubule/autophagy-protective ADNP fragment NAPVSIPQ (NAP). RESULTS: RNA sequencing of spleens, representing a peripheral biomarker source, revealed Tyr-specific sex differences (e.g., cell cycle), accentuated in females (with significant effects on antigen processing and cellular senescence) and corrected by NAP. Differentially expressed, NAP-correctable transcripts, including the autophagy and microbiome resilience-linked FOXO3, were also deregulated in human patient-derived ADNP-mutated lymphoblastoid cells. There were also Tyr sex-specific microbiota signatures. Phenotypically, Tyr mice, similar to patients with ADNP syndrome, exhibited delayed development coupled with sex-dependent gait defects. Speech acquisition delays paralleled sex-specific mouse syntax abnormalities. Anatomically, dendritic spine densities/morphologies were decreased with NAP amelioration. These findings were replicated in the Adnp+/- mouse, including Foxo3 deregulation, required for dendritic spine formation. Grooming duration and nociception threshold (autistic traits) were significantly affected only in males. Early-onset tauopathy was accentuated in males (hippocampus and visual cortex), mimicking humans, and was paralleled by impaired visual evoked potentials and correction by acute NAP treatment. CONCLUSIONS: Tyr mice model ADNP syndrome pathology. The newly discovered ADNP/NAP target FOXO3 controls the autophagy initiator LC3 (microtubule-associated protein 1 light chain 3), with known ADNP binding to LC3 augmented by NAP, protecting against tauopathy. NAP amelioration attests to specificity, with potential for drug development targeting accessible biomarkers.
- MeSH
- autistická porucha * patologie MeSH
- exprese genu MeSH
- homeodoménové proteiny genetika MeSH
- lidé MeSH
- mentální retardace * genetika metabolismus MeSH
- mozek metabolismus MeSH
- myši MeSH
- proteiny nervové tkáně genetika MeSH
- proteiny tau MeSH
- tauopatie * metabolismus MeSH
- zrakové evokované potenciály MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
The aim of the present research has been to determine whether there is a relationship between brain abnormalities found on magnetic resonance imaging (MRI) and autistic psychopathology. A retrospective analysis covering a period between 1998 and 2015 included 489 children with autism (404 boys, 85 girls; average age 8.0 ± 4.2 years) who underwent an MRI of the brain. For clinical diagnosis of autism, the International Classification of Diseases, 10th revision (ICD-10), was used. Autistic psychopathology was evaluated by means of the Autism Diagnostic Interview - Revised. The Spearman nonparametric correlation analysis and chi-square test were used to examine the possible relationships between variables. The group of autistic children did not manifest a statistically significant correlation between the parameters examined on MRI and autistic psychopathology. A correlation between other cysts and repetitive behavior was significant only at trend level (P = 0.054). Gliosis of the brain was significantly more frequent in autistic children with mental retardation than in children without mental retardation (14.1% vs. 7.4%; P = 0.028). Nonmyelinated areas in the brain were significantly more frequent in autistic children with autistic regression than in children without autistic regression (29.9% vs. 15.7%; P = 0.008). Mental retardation was significantly more frequent in autistic children with autistic regression than in children without regression (73.2% vs. 52.5%; P = 0.002). Our research study did not reveal a statistically significant correlation of brain abnormalities on MRI with autistic psychopathology.
- MeSH
- autistická porucha patofyziologie patologie MeSH
- lidé MeSH
- mozek diagnostické zobrazování patologie MeSH
- psychopatologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Sex and gender matter in all aspects of life. Humans exhibit sexual dimorphism in anatomy, physiology, but also pathology. Many of the differences are due to sex chromosomes and, thus, genetics, other due to endocrine factors such as sex hormones, some are of social origin. Over the past decades, huge number of scientific studies have revealed striking sex differences of the human brain with remarkable behavioral and cognitive consequences. Prenatal and postnatal testosterone influence brain structures and functions, respectively. Cognitive sex differences include especially certain spatial and language tasks, but they also affect many other aspects of the neurotypical brain. Sex differences of the brain are also relevant for the pathogenesis of neuropsychiatric disorders such as autism spectrum disorders, which are much more prevalent in the male population. Structural dimorphism in the human brain was well-described, but recent controversies now question its importance. On the other hand, solid evidence exists regarding gender differences in several brain functions. This review tries to summarize the current understanding of the complexity of the effects of testosterone on brain with special focus on their role in the known sex differences in healthy individuals and people in the autism spectrum.
- MeSH
- autistická porucha metabolismus patologie MeSH
- kognice fyziologie MeSH
- lidé MeSH
- mozek účinky léků patologie MeSH
- pohlavní dimorfismus MeSH
- sexuální faktory MeSH
- testosteron metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Previous findings showed that in mice, complete knockout of activity-dependent neuroprotective protein (ADNP) abolishes brain formation, while haploinsufficiency (Adnp+/-) causes cognitive impairments. We hypothesized that mutations in ADNP lead to a developmental/autistic syndrome in children. Indeed, recent phenotypic characterization of children harboring ADNP mutations (ADNP syndrome children) revealed global developmental delays and intellectual disabilities, including speech and motor dysfunctions. Mechanistically, ADNP includes a SIP motif embedded in the ADNP-derived snippet drug candidate NAP (NAPVSIPQ, also known as CP201), which binds to microtubule end-binding protein 3, essential for dendritic spine formation. Here, we established a unique neuronal membrane-tagged, GFP-expressing Adnp+/- mouse line allowing in vivo synaptic pathology quantification. We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment. Adnp+/-mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal). In conclusion, we have connected ADNP-related synaptic pathology to developmental and behavioral outcomes, establishing NAP in vivo target engagement and identifying potential biomarkers. Together, these studies pave a path toward the clinical development of NAP (CP201) for the treatment of ADNP syndrome.
- MeSH
- aminokyselinové motivy MeSH
- autistická porucha genetika metabolismus patologie patofyziologie MeSH
- biologické markery metabolismus MeSH
- buněčná membrána genetika metabolismus patologie MeSH
- chování zvířat MeSH
- dendritické trny metabolismus patologie MeSH
- homeodoménové proteiny MeSH
- lidé MeSH
- mikrotubuly genetika metabolismus patologie MeSH
- modely neurologické * MeSH
- mutace MeSH
- myši knockoutované MeSH
- myši MeSH
- naftochinony farmakologie MeSH
- proteiny nervové tkáně nedostatek MeSH
- regulace genové exprese MeSH
- synapse metabolismus patologie MeSH
- syndrom MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- audiovizuální média MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- MeSH
- arteterapie metody trendy MeSH
- autistická porucha * dějiny diagnóza etiologie klasifikace patologie psychologie MeSH
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- rozvoj osobnosti MeSH
- vývojové poruchy u dětí MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Dětský autismus je jedna z forem pervazivních vývojových poruch. Jedná se o závažné postižení, které ovlivňuje všechny složky osobnosti a provází jedince po celý život. Porucha se vyznačuje především disharmonickým vývojem s převažující poruchou v oblasti sociálních vztahů a komunikace. Měl by být diagnostikován do třetího roku života dítěte, projevuje se však již podstatně dříve, a to mnohdy už do jednoho roku věku. Právě toto rozpoznání časných varovných signálů umožňuje zařadit dítě do rizikové skupiny dětí ohrožených autismem a poskytnout jim adekvátní výchovná a vzdělávací opatření, aby se předešlo zbytečné traumatizaci dítěte i jeho rodiny. V tomto sdělení je kladen důraz na příznaky autismu včetně iniciálních a je apelováno na potřebu jejich časného rozpoznání a zahájení edukace právě v raném dětství, kdy ještě probíhá vývoj a zrání mozku.
- MeSH
- androgeny izolace a purifikace metabolismus škodlivé účinky MeSH
- autistická porucha * genetika patofyziologie patologie MeSH
- genetické nemoci vrozené * diagnóza komplikace MeSH
- hypothalamus enzymologie růst a vývoj MeSH
- lidé MeSH
- mozek enzymologie růst a vývoj MeSH
- nervový systém enzymologie růst a vývoj MeSH
- prenatální poškození enzymologie genetika MeSH
- proteiny nervové tkáně genetika škodlivé účinky MeSH
- testosteron * izolace a purifikace škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Structural neuroimaging studies done by means of magnetic resonance imaging (MRI) have provided important insights into the neurobiological basis for autism. The aim of this article is to review the current state of knowledge regarding structural brain abnormalities in autism. Results of MRI studies dealing with total brain volume, the volume of the cerebellum, caudate nucleus, thalamus, amygdala, hippocampus and the area of the corpus callosum are summarized. Existing research suggests that autistic individuals have larger total brain, cerebellar and caudate nucleus volumes; however, the area of the corpus callosum is reduced. Results of studies involving the amygdala and hippocampus volume in autistic subjects remain inconsistent and no changes have been detected in thalamic volume.
