Atypical Auditory Brainstem Response and Protein Expression Aberrations Related to ASD and Hearing Loss in the Adnp Haploinsufficient Mouse Brain

Hacohen-Kleiman, Gal; Yizhar-Barnea, Ofer; Touloumi, Olga; Lagoudaki, Roza; Avraham, Karen B.; Grigoriadis, Nikolaos; Gozes, Illana

doi:10.1007/s11064-019-02723-6

Cited by 19 publications

(15 citation statements)

References 81 publications

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“…FOXP2, a major transcription factor involved in language acquisition was increased in the hippocampus (Fig. S 2 ), as was seen before also in the haploinsufficient Adnp male mouse hippocampus 33 , with direct association to language acquisition impediments in the ADNP children 6 .…”

Section: Discussionsupporting

confidence: 74%

“…All these genes converge on nervous system development and represent a majority of the tested genes. Interestingly, while expression in testis, pituitary (hypophysis) and thyroid was occasionally similar in trend with the cerebellum, the stomach, kidney and blood exhibited occasionally opposite (increased) trends 33,43 in gene expression associated with the ADNP mutation (Fig. 2, Fig.…”

Section: Adnp Mutant Lymphoblasotoid Rna-seq Supporting Tau Pathologymentioning

confidence: 93%

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Tauopathy in the young autistic brain: novel biomarker and therapeutic target

et al. 2020

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Given our recent discovery of somatic mutations in autism spectrum disorder (ASD)/intellectual disability (ID) genes in postmortem aged Alzheimer's disease brains correlating with increasing tauopathy, it is important to decipher if tauopathy is underlying brain imaging results of atrophy in ASD/ID children. We concentrated on activity-dependent neuroprotective protein (ADNP), a prevalent autism gene. The unique availability of multiple postmortem brain sections of a 7-year-old male, heterozygous for ADNP de novo mutation c.2244Adup/p.His559Glnfs*3 allowed exploration of tauopathy, reflecting on a general unexplored mechanism. The tested subject exhibited autism, fine motor delays, severe intellectual disability and seizures. The patient died after multiple organ failure following liver transplantation. To compare to other ADNP syndrome mutations, immortalized lymphoblastoid cell lines from three different patients (including ADNP p.Arg216*, p.Lys408Valfs*31, and p.Tyr719* heterozygous dominant mutations) and a control were subjected to RNA-seq. Immunohistochemistry, high-throughput gene expression profiles in numerous postmortem tissues followed. Comparisons to a control brain and to extensive datasets were used. Live cell imaging investigated Tau-microtubule interaction, protecting against tauopathy. Extensive child brain tauopathy paralleled by multiple gene expression changes was discovered. Tauopathy was explained by direct mutation effects on Tau-microtubule interaction and correction by the ADNP active snippet NAP. Significant pathway changes (empirical P value < 0.05) included over 100 genes encompassing neuroactive ligand-receptor and cytokine-cytokine receptor interaction, MAPK and calcium signaling, axon guidance and Wnt signaling pathways. Changes were also seen in steroid biosynthesis genes, suggesting sex differences. Selecting the most affected genes by the ADNP mutations for gene expression analysis, in multiple postmortem tissues, identified Tau (MAPT)-gene-related expression changes compared with extensive normal gene expression (RNA-seq) databases. ADNP showed relatively reduced expression in the ADNP syndrome cerebellum, which was also observed for 25 additional genes (representing >50% of the tested genes), including NLGN1, NLGN2, PAX6, SMARCA4, and SNAP25, converging on nervous system development and tauopathy. NAP provided protection against mutated ADNP disrupted Tau-microtubule association. In conclusion, tauopathy may explain brain-imaging findings in ADNP syndrome children and may provide a new direction for the development of tauopathy protecting drug candidates like NAP in ASD/ID.

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Section: Discussionsupporting

confidence: 74%

Section: Adnp Mutant Lymphoblasotoid Rna-seq Supporting Tau Pathologymentioning

confidence: 93%

Tauopathy in the young autistic brain: novel biomarker and therapeutic target

et al. 2020

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“…Additional past studies in the caudal medial mesopallium (CMM) and nidocaudal mesopallium (NCM), two important auditory areas, previously associated these brain areas to perceptual processing of song and the formation of auditory memories (Lynch et al 2013;Haakenson et al 2019). Respectively, this information could align with social and object recognition (visual-based) impairments and audit o r y p a t h w a y a b n o r m a l i t i e s f o l l o w i n g A d n p haploinsufficiency (Vulih-Shultzman et al 2007;Malishkevich et al 2015;Amram et al 2016;Hacohen-Kleiman et al 2018, as well as intellectual disability, autism-like traits, and atypical auditory brain stem response (ABR) in the ADNP syndrome patients (Helsmoortel et al 2014;Hacohen-Kleiman et al 2019;Van Dijck et al 2019). Furthering the association to song, functional connections between caudal medial mesopallium (CMM) and other important regions: HVC, and caudal medial nidopallium (CMN) were suggested to take part in song learning and production in males.…”

Section: Discussionmentioning

confidence: 99%

“…With speech acquisition being a major impediment in ADNP syndrome patients (Gozes et al 2017a;Van Dijck et al 2019), ADNP potential effect on mouse vocal production was tested. A significant sexdependent decline in the number of Adnp +/− mouse pup calls was reported (Hacohen-Kleiman et al 2019), whereas treatment with the ADNP snippet NAP corrected this abnormality (CP201) (Hacohen-Kleiman et al 2018).…”

Section: Introductionmentioning

confidence: 99%

“…In mice, cortical Foxp2 was suggested to be vital for social behavior, causing aberrations in autism-related gene expression and ultrasonic vocalization production (Medvedeva et al 2019). In Adnp +/ − mice, FoxP2 levels were previously shown to increase in the male hippocampus, compared with Adnp +/+ littermates (Hacohen-Kleiman et al 2019), proposing FoxP2 as a potential target for ADNP regulation.…”

Section: Introductionmentioning

confidence: 99%

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Sex-and Region-Dependent Expression of the Autism-Linked ADNP Correlates with Social- and Speech-Related Genes in the Canary Brain

et al. 2020

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The activity-dependent neuroprotective protein (ADNP) syndrome is an autistic-like disorder, instigated by mutations in ADNP. This syndrome is characterized by developmental delays, impairments in speech, motor function, abnormal hearing, and intellectual disabilities. In the Adnp-haploinsufficient mouse model, many of these impediments are evident, appearing in a sex-dependent manner. In zebra finch songbird (ZF; Taeniopygia guttata), an animal model used for song/language studies, ADNP mRNA most robust expression is observed in the cerebrum of young males, potentially corroborating with male ZF exclusive singing behavior and developed cerebral song system. Herein, we report a similar sex-dependent ADNP expression profile, with the highest expression in the cerebrum (qRT-PCR) in the brain of another songbird, the domesticated canary (Serinus canaria domestica). Additional analyses for the mRNA transcripts of the ADNP regulator, vasoactive intestinal peptide (VIP), sister gene ADNP2, and speech-related Forkhead box protein P2 (FoxP2) revealed multiple sex and brain region-dependent positive correlations between the genes (including ADNP). Parallel transcript expression patterns for FoxP2 and VIP were observed alongside specific FoxP2 increase in males compared with females as well as VIP/ADNP2 correlations. In spatial view, a sexually independent extensive form of expression was found for ADNP in the canary cerebrum (RNA in situ hybridization). The songbird cerebral mesopallium area stood out as a potentially high-expressing ADNP tissue, further strengthening the association of ADNP with sense integration and auditory memory formation, previously implicated in mouse and human.

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Tau, ADNP, and sex

Gozes

2023

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With 50 years to the original discovery of Tau, I gave here my perspective, looking through the prism of activity‐dependent neuroprotective protein (ADNP), and the influence of sex. My starting point was vasoactive intestinal peptide (VIP), a regulator of ADNP. I then moved to the original discovery of ADNP and its active neuroprotective site, NAP, drug candidate, davunetide. Tau–ADNP–NAP interactions were then explained with emphasis on sex and future translational medicine.

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Atypical Auditory Brainstem Response and Protein Expression Aberrations Related to ASD and Hearing Loss in the Adnp Haploinsufficient Mouse Brain

Cited by 19 publications

References 81 publications

Tauopathy in the young autistic brain: novel biomarker and therapeutic target

Tauopathy in the young autistic brain: novel biomarker and therapeutic target

Sex-and Region-Dependent Expression of the Autism-Linked ADNP Correlates with Social- and Speech-Related Genes in the Canary Brain

Tau, ADNP, and sex

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