Dataset Information

S-nitrosylation in Shank3 mutated mice

ABSTRACT: We tested the hypothesis that a mutated gene associated with human ASD would generate downstream effects in critical proteins that lead to modification of synaptic functions.

INSTRUMENT(S): 6520 Quadrupole Time-of-Flight LC/MS

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Haitham Amal

LAB HEAD: Prof. Steven R. Tannenbaum

PROVIDER: PXD006907 | Pride | 2018-10-02

REPOSITORIES: Pride

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Publications

Shank3 mutation in a mouse model of autism leads to changes in the S-nitroso-proteome and affects key proteins involved in vesicle release and synaptic function.

Amal Haitham H Barak Boaz B Bhat Vadiraja V Gong Guanyu G Joughin Brian A BA Wang Xin X Wishnok John S JS Feng Guoping G Tannenbaum Steven R SR

Molecular psychiatry 20180709 8

Mutation in the SHANK3 human gene leads to different neuropsychiatric diseases including Autism Spectrum Disorder (ASD), intellectual disabilities and Phelan-McDermid syndrome. Shank3 disruption in mice leads to dysfunction of synaptic transmission, behavior, and development. Protein S-nitrosylation, the nitric oxide (NO<sup>•</sup>)-mediated posttranslational modification (PTM) of cysteine thiols (SNO), modulates the activity of proteins that regulate key signaling pathways. We tested the hypot ...[more]

PMID: 29988084

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Project description:Rett syndrome (RTT) is a neurodevelopmental disorder characterized by developmental regression around 6-18 months after birth, followed by a lifetime of intellectual disability, stereotyped behaviors, and motor deficits. RTT is caused by mutations in MeCP2, a methyl-CpG binding protein that was traditionally believed to repress gene expression. Gene expression studies of individual brain regions, however, have revealed that MeCP2 loss-of-function leads to the subtle activation and repression of its gene targets. However, these results may be confounded by the extensive neuronal cell heterogeneity inherent in these brain structures. To minimalize this issue of heterogeneity, we assessed whether Mecp2-null mice exhibited alterations in gene expression patterns in the striatum, a brain nucleus with relatively homogenous neuronal types and is highly relevant to the motor deficits observed in RTT. Despite the homogeneity of the tissue, the fold-change of the 127 differentially expressed genes we identified remained low with a mean change consistent with other studies. However, many of those genes differentially expressed in the striatum have not been previously identified in gene expression analyses of other brain regions. This suggests therefore that the differential expression of genes following loss of MeCP2 occurs in a tissue, or cell-type specific manner and thus MeCP2 function should be understood in a cellular context. In initiating this study, we reasoned that reducing the number of cell types in a microarray experiment may reveal transcriptional changes that are masked in a whole tissue analysis. We therefore focused on tissues more homogeneous in regards to the diversity of neuronal cell types they contain in order to discern gene expression changes in the absence of MeCP2. We chose to isolate the striatum, a tissue composed predominantly of GABAergic medium spiny neurons (MSNs). The striatum was resected from five symptomatic Mecp2-null (KO) male mice bearing the Bird allele and five wild-type (WT) littermates in a C57BL/6 background. We also isolated liver from the same individuals to serve as a non-neuronal control. RNA was isolated from these tissues, converted to cDNA, and hybridized to a single-channel Affymetrix GeneChip Mouse Exon 1.0 ST array for a total of 20 individual arrays.

Dataset Information

S-nitrosylation in Shank3 mutated mice

Publications

Shank3 mutation in a mouse model of autism leads to changes in the S-nitroso-proteome and affects key proteins involved in vesicle release and synaptic function.

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