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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): 6520A 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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			Action	DRS
	4m_Cor_KO_1st.d.zip	Other
	4m_Cor_KO_2nd.d.zip	Other
	4m_Cor_WT_1st.d.zip	Other
	4m_Cor_WT_2nd.d.zip	Other
	4m_Str_KO_1st.d.zip	Other

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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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Metabolic bypass partially rescues S-nitrosylation-induced TCA cycle inhibition and synapse loss in Alzheimer’s disease human neurons

Project description:In Alzheimer’s disease (AD), dysfunctional mitochondrial metabolism has been associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild-type and AD mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN), we found evidence for compromised mitochondrial energy production in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). By isotope-labeled metabolic flux experiments, a major block in activity occurred in the tricarboxylic acid (TCA) cycle at the -ketoglutarate dehydrogenase (KGDH)/succinyl coenzyme-A synthetase step, metabolizing -ketoglutarate to succinate. Associated with this block we found aberrant protein S-nitrosylation of KGDH subunits that are known to inhibit enzyme function. This aberrant S-nitrosylation was documented not only in AD-hiN but also in postmortem human AD brains vs. controls, as assessed by two separate unbiased mass spectrometry platforms using both SNOTRAP identification of S-nitrosothiols and chemoselective-enrichment of S-nitrosoproteins. Treatment with dimethyl succinate a cell-permeable derivative of a TCA substrate downstream to the block resulted in partial rescue of mitochondrial bioenergetic function as well as improvement in synapse number in AD-hiN. Our findings have therapeutic implications as proof-of-principle that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC-based models of AD.

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(Phospho)Proteomic Characterization of Ptenm3m4 Cortex

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Unbiased proteomic analysis of postsynaptic density fractions from Shank3 mutant mice reveals brain region specific changes highly relevant to autism spectrum disorder

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