Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer’s Disease

Wan, Lily; Ai, Jia-Qi; Yang, Chen; Jiang, Juan; Zhang, Qilei; Luo, Zhaohui; Huang, Rou-Jie; Tu, Tian Ming; Pan, Aihua; Tu, Ewen; Manavis, Jim; Xiao, Bo; Yan, Xiao‐Xin

doi:10.3389/fnagi.2021.717263

Cited by 11 publications

(15 citation statements)

References 107 publications

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“…Motor centers of the brain include the motor cortex, basal ganglia, thalamus, and cerebellum. These are all areas that strongly express SHANK3 in an isoform-specific manner ( Peça et al, 2011 ; Wang et al, 2014 ) in both mice and human brains ( Wan et al, 2021 ). In a previous study, grooming was shown to occur in another isoform-specific KO of Shank3 , at a stage corresponding to early childhood.…”

Section: Discussionmentioning

confidence: 99%

Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders

Bauer

Delling²,

Bockmann³

et al. 2023

Front. Behav. Neurosci.

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Individuals with a SHANK3-related neurodevelopmental disorder, also termed Phelan-McDermid syndrome or abbreviated as PMS, exhibit significant global developmental delay, language impairment, and muscular hypotonia. Also common are repetitive behaviors and altered social interactions, in line with a diagnosis of autism spectrum disorders. This study investigated the developmental aspect of autism-related behaviors and other phenotypes in a Shank3-transgenic mouse model. The animals underwent two sets of identical behavioral experiments, spanning motor skills, social and repetitive behavior, and cognition: baseline began at 5 weeks of age, corresponding to human adolescence, and the follow-up was initiated when aged 13 weeks, resembling early adulthood in humans. Interestingly, the animals displayed relatively stable phenotypes. Moreover, motor coordination and endurance were impaired, while muscle strength was unchanged. Surprisingly, the animals displayed only minor impairments in social behavior, but pronounced stereotypic and repetitive behaviors. Some behavioral tests indicated increased avoidance and anxiety. While spatial learning and memory were unchanged, knockout animals displayed slightly impaired cognitive flexibility. Female animals had similar abnormalities as males in the paradigms testing avoidance, anxiety, and cognition, but were less pathological in motor function and repetitive behavior. In all test paradigms, heterozygous Shank3 knockout animals had either no abnormal or a milder phenotype. Accurate characterization of animal models for genetic diseases is a prerequisite for understanding the pathophysiology. This is subsequently the basis for finding suitable and, ideally, translational biomarkers for therapeutic approaches and, thereby reducing the number of animals needed for preclinical trials.

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Section: Discussionmentioning

confidence: 99%

Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders

Bauer

Delling²,

Bockmann³

et al. 2023

Front. Behav. Neurosci.

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“…In this study, we focused on synaptic SHANK3 expression, but SHANK3 does not only localize to synapses but is also expressed in the nucleus ( Grabrucker et al, 2014 ) and the cytoplasm ( Wang et al, 2014 ). However, synaptic SHANK3 expression is best studied and offers a clear structure for analysis, as shown with different SHANK3 antibodies in the literature ( Arons et al, 2012 ; Han et al, 2016 ; Kerrisk Campbell and Sheng, 2018 ; Wan et al, 2021 ). In respect of synaptic localization, the vNterm SHANK3 antibody can offer new insights.…”

Section: Discussionmentioning

confidence: 99%

SHANK3 Antibody Validation: Differential Performance in Western Blotting, Immunocyto- and Immunohistochemistry

Lutz

Bauer

Ioannidis

et al. 2022

Front. Synaptic Neurosci.

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SHANK3 is a scaffolding protein implicated in autism spectrum disorders (ASD). Its function at excitatory glutamatergic synapses has been studied for the last two decades, however, tissue-specific expression patterns as well as its subcellular localization need to be studied in further detail. Especially the close sequence homology of SHANK3 to its protein family members SHANK2 and SHANK1 raises the emerging need for specific antibodies that are validated for the desired methodology. With this study, we aim to validate a set of commercial as well as homemade SHANK3 antibodies in Western Blotting, and synaptic immunocyto- and immunohistochemistry. We found that only a small subset of the antibodies included in this study meet the criteria of quality and specificity. Therefore, we aim to share our findings on SHANK3 antibody validation but also raise awareness of the necessity of antibody specificity testing in the field.

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“…26 10 -5 ) (Figure S12C). These genes * * are associated with autophagy (56,57), protein ubiquitination (58), and synaptic plasticity (59,60), which are well-established biological functions associated with AD. Of note, ZNF385A (p=8.82 10 -1 for next_Aβ) and SUSD6 (p=2.94 10 -2 for next_Aβ) were not * * previously identified as statistically significant DEGs in any of the 7 spatially resolved pathological categories when Aβ and next_Aβ spots were not collapsed (Figure S12D).…”

Section: * *mentioning

confidence: 99%

Influence of Alzheimer’s disease related neuropathology on local microenvironment gene expression in the human inferior temporal cortex

Kwon

Parthiban

Tippani

et al. 2023

Preprint

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Neuropathological lesions in the brains of individuals affected with neurodegenerative disorders are hypothesized to trigger molecular and cellular processes that disturb homeostasis of local microenvironments. Here, we applied the 10x Genomics Visium Spatial Proteogenomics (Visium-SPG) platform, which measures spatial gene expression coupled with immunofluorescence protein co-detection, in post-mortem human brain tissue from individuals with late-stage Alzheimer's disease (AD) to investigate changes in spatial gene expression with respect to amyloid-β (Aβ) and hyperphosphorylated tau (pTau) pathology. We identified Aβ-associated transcriptomic signatures in the human inferior temporal cortex (ITC) during late-stage AD, which we further investigated at cellular resolution with combined immunofluorescence and single molecule fluorescent in situ hybridization (smFISH) co-detection technology. We present a workflow for analysis of Visium-SPG data and demonstrate the power of multi-omic profiling to identify spatially-localized changes in molecular dynamics that are linked to pathology in human brain disease. We provide the scientific community with web-based, interactive resources to access the datasets of the spatially resolved AD-related transcriptomes at https://research.libd.org/Visium_SPG_AD/.

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Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer’s Disease

Cited by 11 publications

References 107 publications

Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders

Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders

SHANK3 Antibody Validation: Differential Performance in Western Blotting, Immunocyto- and Immunohistochemistry

Influence of Alzheimer’s disease related neuropathology on local microenvironment gene expression in the human inferior temporal cortex

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