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TMT mass spectrometry analysis of wild type and Cdkl5 null mouse CSF of animals aged 46 days

ABSTRACT: TMT mass spectrometry analysis of wild type and Cdkl5 null mouse CSF of animals aged 46 dayss

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cerebrospinal Fluid

SUBMITTER: Duc Duong

LAB HEAD: Victor Faundez

PROVIDER: PXD029811 | Pride | 2022-10-14

REPOSITORIES: Pride

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			Action	DRS
	vf_cdlk_mcsftmt_01.raw	Raw
	vf_cdlk_mcsftmt_02.raw	Raw
	vf_cdlk_mcsftmt_03.raw	Raw
	vf_cdlk_mcsftmt_04.raw	Raw
	vf_cdlk_mcsftmt_05.raw	Raw

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Publications

Convergent cerebrospinal fluid proteomes and metabolic ontologies in humans and animal models of Rett syndrome.

Zlatic Stephanie A SA Duong Duc D Gadalla Kamal K E KKE Murage Brenda B Ping Lingyan L Shah Ruth R Fink James J JJ Khwaja Omar O Swanson Lindsay C LC Sahin Mustafa M Rayaprolu Sruti S Kumar Prateek P Rangaraju Srikant S Bird Adrian A Tarquinio Daniel D Carpenter Randall R Cobb Stuart S Faundez Victor V

iScience 20220817 9

MECP2 loss-of-function mutations cause Rett syndrome, a neurodevelopmental disorder resulting from a disrupted brain transcriptome. How these transcriptional defects are decoded into a disease proteome remains unknown. We studied the proteome of Rett cerebrospinal fluid (CSF) to identify consensus Rett proteome and ontologies shared across three species. Rett CSF proteomes enriched proteins annotated to HDL lipoproteins, complement, mitochondria, citrate/pyruvate metabolism, synapse compartments ...[more]

PMID: 36060065

Similar Datasets

TMT mass spectrometry analysis of wild type and Mecp2 null mouse CSF of animals aged 46 days

Project description:TMT mass spectrometry analysis of wild type and Mecp2 null mouse CSF of animals aged 46 days

2022-10-14 | PXD029809 | Pride

TMT mass spectrometry analysis of wild type and Mecp2 null rat CSF of animals aged 23-26 days

Project description:TMT mass spectrometry analysis of wild type and Mecp2 null rat CSF of animals aged 23-26 days

2022-10-14 | PXD029808 | Pride

Expression profiling in WT vs CDKL5 mutated IPSCs

Project description:Mutations in the human CDKL5 gene have been associated with early onset seizure variant of Rett Syndrome. In order to investigate the potential involvement of CDKL5 in the regulation of gene expression, we compared expression profiles in WT vs CDKL5-mutated IPS clones from two patients (one male and one female) with different mutations using two-colour microarray experiments. For the female patient (CDKL5 mutation p.Gln347X) we compared one clone expressing the mutant CDKL5 allele to another clone from the same patient that expresses the wild-type allele. Maintenance of X chromosome inactivation and the resulting mono-allelic expression of CDKL5 were confirmed by androgen receptor assay and direct sequencing of CDKL5 mRNA. The clone derived from the male patient (CDKL5 mutation p.Thr288Ile) was compared to a clone derived from a normal newborn male. For each mutant/control pair four technical replicates were performed for a total of eight chip hybridizations.

2014-07-02 | E-MTAB-2223 | biostudies-arrayexpress

Transcription profiling by array of human clonal primary fibroblasts from patients with CDKL5 mutations

Project description:Mutations in the human CDKL5 gene have been shown to cause infantile spasms, as well as Rett syndrome-like phenotype. Because CDKL5 is subjected to X chromosome inactivation (XCI), individual cells from CDKL5 mutation girls either express the wild-type or mutant allele, likely resulting in different consequences at both the cellular and molecular levels. To identify these consequences, we carried out gene expression profiling on clonal populations derived from primary cultures of three patientsM-^R fibroblasts expressing either allele. A total of 16 up-regulated and 20 down-regulated genes were identified. The differentially expressed gene products, mostly involved in differentiation and oxidative stress may be related to a mechanism underlying mental retardation and epilepsy. Among these differentially expressed proteins, the apoptosis signal-regulated kinase MAP3K5 expression was found to be altered in non-neuronal, but also in neuronal CDKL5 deficient cells. Due to the fact that MAP3K5 activates MAP kinase pathway, which mediates signals leading to both differentiation and survival in neuronal cells, we suggest that a CDKL5 deficit may induce changes in synaptic plasticity in patientM-^Rs brain.

2011-07-23 | E-MEXP-2833 | biostudies-arrayexpress

Quantitative phosphoproteomic for CDKL5 substrates

Project description:Global phosphoproteomic screen to identify the first cellular substrates of CDKL5. CDKL5 knock-out U2OS cells and CDKL5 wt U2OS cells were generated for the TMT-based phosphoproteomic. Thi leads to the identification and further validation of several phosphopetides of MAP1S, CEP131 and CDKL5 itself. The phosphoproteomic analysis allowed the identification of the first cellular substrates for CDKL5 kinase.

2018-09-24 | PXD009374 | Pride

INPP5D regulates inflammasome activation in human microglia

Project description:Microglia and neuroinflammation play an important role in the development and progression of Alzheimer’s disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses of RNA and protein profiles in INPP5D-disrupted iPSC-derived human microglia, we find that reduction in INPP5D activity is associated with molecular profiles consistent with disrupted autophagy and inflammasome activation. These findings are validated through targeted pharmacological experiments which demonstrate that reduced INPP5D activity induces the formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1 and IL-18. Further, in-depth analyses of human brain tissue across hundreds of individuals using a multi-analytic approach provides evidence that a reduction in function of INPP5D in microglia results in inflammasome activation in AD. These findings provide insights into the molecular mechanisms underlying microglia-mediated processes in AD and highlight the inflammasome as a potential therapeutic target for modulating INPP5D-mediated vulnerability to AD.

2024-01-26 | PXD046040 | Pride

Heterogeneous Expression of Nuclear Encoded Mitochondrial Genes Distinguishes Inhibitory and Excitatory Neurons.

Project description:Mitochondrial composition varies by organ and their constituent cell types. This mitochondrial diversity likely determines variations in mitochondrial function. However, the heterogeneity of mitochondria in the brain remains underexplored despite the large diversity of cell types in neuronal tissue. Here, we used molecular systems biology tools to address whether mitochondrial composition varies by brain region and neuronal cell type. We reasoned that proteomics and transcriptomics of microdissected brain regions combined with analysis of single cell mRNA sequencing could reveal the extent of mitochondrial compositional diversity. We selected nuclear encoded gene products forming complexes of fixed stoichiometry, such as the respiratory chain complexes and the mitochondrial ribosome, as well as molecules likely to perform their function as monomers, such as the family of SLC25 transporters. We found that only the proteome encompassing these nuclear-encoded mitochondrial genes and obtained from microdissected brain tissue segregated the hippocampus, striatum, and cortex from each other. Nuclear-encoded mitochondrial transcripts could only segregate cell types and brain regions when the analysis was performed at the single cell level. In fact, single cell mitochondrial transcriptomes were able to distinguish glutamatergic and distinct types of GABAergic neurons from one another. Within these cell categories, unique SLC25A transporters were able to identify distinct cell subpopulations. Our results demonstrate heterogeneous mitochondrial composition across brain regions and cell types. We postulate that mitochondrial heterogeneity influences regional and cell type specific mechanisms in health and disease.

2022-02-17 | PXD026104 | Pride

SORL1 regulates APOE and CLU levels in human neurons

Project description:SORL1 is implicated in the pathogenesis of Alzheimer’s disease (AD) through genetic studies. To interrogate the role(s) of SORL1 in human brain cells, SORL1 null iPSCs are differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 leads to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. SORL1 loss induces a neuron-specific reduction in APOE and CLU and altered lipid profiles. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1 null neurons but does not rescue APOE levels. Pathway analyses implicate TGF-β/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in post-mortem brain. These studies provide a mechanistic link between strong genetic risk factors for AD.

2023-10-24 | PXD044093 | Pride

CDKL5 substrates - Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase

Project description:Identification of CDKL5 substrates. Immuno-precipitated proteins were TMT labelled and analysed via LC-MS/MS.

2018-10-02 | PXD009327 | Pride

Chemical genetic identification of CDKL5 substrates reveals its role in neuronal microtubule dynamics

Project description:Loss-of-function mutations in CDKL5 kinase causes severe neurodevelopmental delay and early-onset seizures. Identification of CDKL5 substrates is key to understanding its function. Using chemical genetics, we found that CDKL5 phosphorylates three microtubule-associated proteins: MAP1S, EB2 and ARHGEF2, and determined the phosphorylation sites. Substrate phosphorylations are greatly reduced in CDKL5 knockout mice, verifying these as physiological substrates. In CDKL5 knockout mouse neurons, dendritic microtubules have longer EB3-labelled plus-end growth duration and these altered dynamics are rescued by reduction of MAP1S levels through shRNA expression, indicating that CDKL5 regulates microtubule dynamics via phosphorylation of MAP1S. We show that phosphorylation by CDKL5 is required for MAP1S dissociation from microtubules. Additionally, anterograde cargo trafficking is compromised in CDKL5 knockout mouse dendrites. Finally, EB2 phosphorylation is reduced in patient-derived human neurons. Our results reveal a novel activity-dependent molecular pathway in dendritic microtubule regulation and suggest a pathological mechanism which may contribute to CDKL5 deficiency disorder.

2018-09-18 | PXD010511 | Pride

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