Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life / Jessica A. JIMÉNEZ in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 74 p. Titre : Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life Type de document : Texte imprimé et/ou numérique Auteurs : Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur Article en page(s) : 74 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Brain overgrowth  Chd8  Endoplasmic reticulum stress  Macrocephaly  Unfolded protein response Index. décimale : PER Périodiques Résumé : BACKGROUND: Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. METHODS: We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12?months). RESULTS: Chd8(V986*/+) mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8(V986*/+) mutant mice at 1?year of age. Pup survival was reduced in wild-type x Chd8(V986*/+) crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8(V986*/+) mice and then equalized relative to wild-type mice in the postnatal period. At 12?months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8(V986*/+) mice, whereas genes associated with the c-MET signaling pathway were increased in expression. LIMITATIONS: It is unclear whether the transcriptional changes observed with age in Chd8(V986*/+) mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. CONCLUSIONS: Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8(V986*/+) mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8(V986*/+) mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice. En ligne : http://dx.doi.org/10.1186/s13229-020-00369-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life [Texte imprimé et/ou numérique] / Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur . - 74 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 74 p. Mots-clés : Autism spectrum disorder  Brain overgrowth  Chd8  Endoplasmic reticulum stress  Macrocephaly  Unfolded protein response Index. décimale : PER Périodiques Résumé : BACKGROUND: Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. METHODS: We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12?months). RESULTS: Chd8(V986*/+) mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8(V986*/+) mutant mice at 1?year of age. Pup survival was reduced in wild-type x Chd8(V986*/+) crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8(V986*/+) mice and then equalized relative to wild-type mice in the postnatal period. At 12?months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8(V986*/+) mice, whereas genes associated with the c-MET signaling pathway were increased in expression. LIMITATIONS: It is unclear whether the transcriptional changes observed with age in Chd8(V986*/+) mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. CONCLUSIONS: Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8(V986*/+) mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8(V986*/+) mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice. En ligne : http://dx.doi.org/10.1186/s13229-020-00369-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Prenatal treatment path for angelman syndrome and other neurodevelopmental disorders / Mark J. ZYLKA in Autism Research, 13-1 (January 2020)  

Public ISBD [article]  inAutism Research > 13-1 (January 2020) . - p.11-17 Titre : Prenatal treatment path for angelman syndrome and other neurodevelopmental disorders Type de document : Texte imprimé et/ou numérique Auteurs : Mark J. ZYLKA, Auteur Article en page(s) : p.11-17 Langues : Anglais (eng) Mots-clés : autism spectrum disorder  birth weight  case-control study  epidemiology  risk markers Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by mutation or deletion of the maternally inherited UBE3A allele. These pathogenic mutations lead to loss of maternal UBE3A expression in neurons. Antisense oligonucleotides and gene therapies are in development, which activate the intact but epigenetically silenced paternal UBE3A allele. Preclinical studies indicate that treating during the prenatal period could greatly reduce the severity of symptoms or prevent AS from developing. Genetic tests can detect the chromosome 15q11-q13 deletion that is the most common cause of AS. New, highly sensitive noninvasive prenatal tests that take advantage of single-cell genome sequencing technologies are expected to enter the clinic in the coming years and make early genetic diagnosis of AS more common. Efforts are needed to identify fetuses and newborns with maternal 15q11-q13 deletions and to phenotype these babies relative to neurotypical controls. Clinical and parent observations suggest AS symptoms are detectable in infants, including reports of problems with feeding and motor function. Quantitative phenotypes in the 0- to 1-year age range will permit a more rapid assessment of efficacy when future treatments are administered prenatally or shortly after birth. Although prenatal therapies are currently not available for AS, prenatal testing combined with prenatal treatment has the potential to revolutionize how clinicians detect and treat babies before they are symptomatic. This pioneering prenatal treatment path for AS will lay the foundation for treating other syndromic neurodevelopmental disorders. Autism Res 2020, 13: 11-17. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Prenatal treatment could benefit expectant parents whose babies test positive for the chromosome microdeletion that causes Angelman syndrome (AS). Prenatal treatment is predicted to have better outcomes than treating after symptoms develop and may even prevent AS altogether. This approach could generally be applied to the treatment of other syndromic neurodevelopmental disorders. En ligne : http://dx.doi.org/10.1002/aur.2203 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=415 [article] Prenatal treatment path for angelman syndrome and other neurodevelopmental disorders [Texte imprimé et/ou numérique] / Mark J. ZYLKA, Auteur . - p.11-17. Langues : Anglais (eng) in Autism Research > 13-1 (January 2020) . - p.11-17 Mots-clés : autism spectrum disorder  birth weight  case-control study  epidemiology  risk markers Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by mutation or deletion of the maternally inherited UBE3A allele. These pathogenic mutations lead to loss of maternal UBE3A expression in neurons. Antisense oligonucleotides and gene therapies are in development, which activate the intact but epigenetically silenced paternal UBE3A allele. Preclinical studies indicate that treating during the prenatal period could greatly reduce the severity of symptoms or prevent AS from developing. Genetic tests can detect the chromosome 15q11-q13 deletion that is the most common cause of AS. New, highly sensitive noninvasive prenatal tests that take advantage of single-cell genome sequencing technologies are expected to enter the clinic in the coming years and make early genetic diagnosis of AS more common. Efforts are needed to identify fetuses and newborns with maternal 15q11-q13 deletions and to phenotype these babies relative to neurotypical controls. Clinical and parent observations suggest AS symptoms are detectable in infants, including reports of problems with feeding and motor function. Quantitative phenotypes in the 0- to 1-year age range will permit a more rapid assessment of efficacy when future treatments are administered prenatally or shortly after birth. Although prenatal therapies are currently not available for AS, prenatal testing combined with prenatal treatment has the potential to revolutionize how clinicians detect and treat babies before they are symptomatic. This pioneering prenatal treatment path for AS will lay the foundation for treating other syndromic neurodevelopmental disorders. Autism Res 2020, 13: 11-17. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Prenatal treatment could benefit expectant parents whose babies test positive for the chromosome microdeletion that causes Angelman syndrome (AS). Prenatal treatment is predicted to have better outcomes than treating after symptoms develop and may even prevent AS altogether. This approach could generally be applied to the treatment of other syndromic neurodevelopmental disorders. En ligne : http://dx.doi.org/10.1002/aur.2203 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=415

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